The prevalence of diabetes mellitus (DM) was higher in primary aldosteronism (PA) patients. We aimed to evaluate the outcome of DM after adrenalectomy and determine the factors associated with that in PA patients.PA patients with DM (PA + DM patients) who received adrenalectomy were recruited into the study. The patients were classified into 3 groups based on their DM conditions after treatment, including “remission”, “improved” and “unchanged” groups. Univariate and multivariate logistic regression analysis was conducted to uncover the preoperative factors affecting the outcome of DM after adrenalectomy.P = 0.029). Higher concentration of urinary magnesium (P = 0.031) and higher 24 h urinary potassium (P = 0.049) were factors negatively associated with the “remission” from DM after adrenalectomy.A total of 54 PA + DM patients received adrenalectomy. After adrenalectomy, 16.7%, 33.3% and 50.0% of patients were classified into the “remission”, “improved” and “unchanged” groups, respectively. The factors negatively associated with remission or improvement from DM after adrenalectomy were longer duration of hypertension (Adrenalectomy was beneficial for the remission and improvement from DM in the half of PA patients with DM. Longer duration of hypertension, higher concentration of urinary magnesium and higher 24 h urinary potassium may prevent the remission and improvement from DM after adrenalectomy in PA patients. Examination of urinary electrolyte could be considered in PA patients with DM for predicting the outcome of DM after adrenalectomy.The online version contains supplementary material available at 10.1186/s12902-022-01254-6. Primary aldosteronism (PA) is characterized by hypertension, excessive aldosterone excretion and low serum potassium. Its prevalence in hypertensive populations ranges from 4–10% . The preThis retrospective study was conducted following the Strengthening the Reporting of Observational Studies in Epidemiology guideline . The WesWe selected PA patients with DM who received adrenal venous sampling from January 2018 to January 2021 at our institute. PA was diagnosed using the American Endocrine Society guideline . DM was Demographics, medical history information, and preoperative laboratory test results were extracted from the medical records of PA patients with DM. Demographic factors included body mass index (BMI), gender and age. Medical history information included the maximal systolic blood pressure, duration of hypertension and DM, side and size of tumor and clinical symptoms. The results of laboratory tests before adrenalectomy were also collected, including renin-angiotensin-aldosterone system factors, urinary and blood electrolytes, factors of glucocorticoid metabolism, routine blood tests, hepatic and renal function factors, lipids and glucose metabolism indices. Fasting blood glucose and glycosylated hemoglobin (HbA1C) before surgery were also examined. Biochemical examinations were performed with a Roche Cobas 8000. Renin and aldosterone were examined with radioimmunoassay. Briefly, serum was incubated with a solid phase anti-aldosterone or anti-renin monoclonal antibody at 37℃ for 1 h. Then, unbound material was removed. The concentrations of renin and aldosterone were calculated according to standard curves. The intra-assay coefficient of variation (CV) was < 10.4%, and the inter-assay CV was < 15.6%.PA patients with DM were followed up to obtain DM and hypertension conditions one year after adrenalectomy. They also received examinations of fasting blood glucose and HbA1C. First, we separated the patients into 3 groups according to the use of antidiabetic medications. Patients in the “remission” group were not taking antidiabetic medications any longer and the fasting blood glucose and HbA1C were within the normal range. The following conditions were considered as “improved”. First, patients had fewer types of antidiabetic medications than before or fewer doses of medications (without any change of types of medications), while the fasting blood glucose or HbA1C was the same or lower than before. Second, the types of antidiabetic medications did not change, but the fasting blood glucose or HbA1C was within the normal range after treatment. The remaining patients were classified as “unchanged”. Similarly, they were also divided into three groups according to their antihypertensive medications after treatment. The “remission”, “improved” and “unchanged” groups included patients having no, less, and the same or more medications to maintain blood pressure within a normal range after treatment, respectively.P values < 0.05 was considered significantly different.Categorical variables were presented as quantity (percentage) and were analyzed using Fisher’s exact test or Chi-square test. Quantitative variables were reported as the mean (standard deviation) if they were symmetrically distributed; otherwise, they were presented as median (interquartile range). Quantitative variables were analyzed by the Kruskal-Wallis test or analysis of variance (ANOVA) between three groups and by Mann-Whitney test or Student’s t-test between two groups. Univariate and multivariate logistic regression analyses were conducted to identify the parameters affecting the remission and improvement from DM. Statistical analyses were conducted using AKIBM SPSS Statistics 24.0 . 2. The number of males (n = 34) accounted for 63% of all the PA patients with DM. One year after adrenalectomy, 9 (16.7%) “remission” patients did not need antidiabetic medications any longer, and their fasting blood glucose and HbA1C levels were within the normal ranges; 18 (33.3%) “improved” patients had lower fasting blood glucose or HbA1C levels after surgery, while they needed fewer types or doses of antidiabetic medications. The remaining 27 (50.0%) “unchanged” patients maintained the same therapy for DM as before and their fasting blood glucose and HbA1C levels did not decrease after surgery (Supplementary Table P = 0.428). After adrenalectomy, both the median fasting blood glucose  and median HbA1C  levels were lower than those before surgery. The median fasting blood glucose (P = 0.398) and median HbA1C (P = 0.068) before surgery were not significantly different between three groups. However, the median fasting blood glucose was lower in the “remission” group (5.23 mmol/L), followed by the “improved” group (6.15 mmol/L) and “unchanged” (7.08 mmol/L) group after surgery (P = 0.001). Median HbA1C was also lower in the “remission” group (5.70%) than in the “improved” group (6.45%) and “unchanged” group (6.50%) (P = 0.001). After surgery, the mean serum potassium levels of all patients were higher than 3.5 mmol/L. All the patients’ median plasma aldosterone levels (lying or standing position) and median ARRs dropped below the upper limit of normal.In all, 321 PA patients received adrenal venous sampling at our institute. Among them, 63 (19.6%) PA patients had DM, and 54 (85.7%) of them were available for follow-ups (Table P < 0.05). Then, variables with P < 0.10 were entered into the multivariate logistic regression analysis, including duration of hypertension, red blood cell, platelet, alkaline phosphatase, concentration of urinary sodium and 24 h urinary phosphorus. Fasting blood glucose before surgery was also taken into consideration when multivariate logistic regression analysis was performed because it was lower in the “remission” patients. The results showed that PA + DM patients with longer duration of hypertension (odds ratio (OR) = 1.020, 95% confidence interval (CI) 1.002–1.039, P = 0.029) were less likely to achieve remission or improvement from DM after adrenalectomy.The remission and improved groups were considered as a whole group and compared with the unchanged group Table . VariablP < 0.10, including age, red blood cell, eGFR, concentration of urinary potassium, concentration of urinary magnesium and 24 h urinary potassium by multivariate logistic regression analysis, we found that higher concentration of urinary magnesium  and higher 24 h urinary potassium  were factors negatively associated with the “remission” from DM after adrenalectomy in PA patients.We also compared the remission group with the other two groups Table . UnivariSome studies have analyzed the changes in blood glucose and insulin sensitivity in PA patients after adrenalectomy. Most studies found that blood glucose did not decrease , 9, 10. Our study found that 16.7% of PA + DM patients have achieved remission from DM, and 33.3% of patients were considered “improved” from DM after adrenalectomy, which emphasized the importance of the early identification of PA in DM patients who need adrenalectomy to achieve remission or improvement from DM. Similarly, some studies reported that fasting plasma glucose decreased and insulin sensitivity increased after adrenalectomy , 10, 16.Apart from high blood aldosterone, low blood potassium was another typical feature of PA. Our study revealed that higher 24 h urinary potassium (K) was a factor negatively associated with the “remission” from DM after adrenalectomy in PA patients. However, the blood potassium was not statistically different between three groups. The reason for this phenomenon might be that PA patients would receive oral supplement of potassium before preoperative examination, while low blood potassium induced by high blood aldosterone had lasted for a long time. Some studies reported that there was an inverse relationship between blood potassium level and risk of DM , 21. RowOur study found that the duration of hypertension was much longer in the unchanged group, indicating that a longer duration of hypertension prevented the remission or improvement from DM after adrenalectomy in PA patients. However, the remission or improvement from hypertension did not influence the remission or improvement from DM after adrenalectomy. Although PA can affect patients at any age, studies have reported that PA was commonly diagnosed approximately 50 years old, which indicated the late recognition of PA and its negative effects on DM . PatientMultivariate logistic regression analyses revealed that higher 24 h urinary magnesium prevented the remission from DM after adrenalectomy. The possible mechanism may be associated with the expansion of the extravascular space, which prevents the reabsorption of magnesium in the proximal tubules, resulting in their excessive excretion from urine . To mainThere were some limitations to the study. First, the sample size was small, and the age was statistically lower in remission group, all which may cause biases and affect the statistical analysis. Second, this was a retrospective study, which may cause biases when analyzing the factors affecting the outcome of DM after adrenalectomy. More prospective randomized studies are needed to verify whether adrenalectomy could improve glucose metabolism and which factors are associated with the blood glucose after adrenalectomy.Adrenalectomy was beneficial for the remission and improvement from DM in the half of PA patients with DM. Longer duration of hypertension, higher concentration of urinary magnesium and higher 24 h urinary potassium may prevent the remission and improvement from DM after adrenalectomy in PA patients. Examination of urinary electrolyte could be considered in PA patients with DM for predicting the outcome of DM after adrenalectomy.Additional file 1:Table 1. The drugs used to treat diabetes mellitus before and after adrenalectomy.


Combined solid organ transplantation is infrequently performed in Brazil. The objective of this article is to present our initial experience with combined heart and kidney transplantation.From January 2007 to December 2019, four patients were submitted to combined heart and kidney transplantation. Their mean age was 55.7±4.4 years, and three (75%) patients were males. All patients had Chagas cardiomyopathy, two were hospitalized and inotrope dependent, and all patients were on preoperative dialysis (median of 12 months prior to transplant).All patients survived and were in New York Heart Association functional class I at the latest follow-up (mean 34.7±17.5 months). Mean retarded kidney graft function was 22.9±9.7 days. One patient lost the kidney graft two years after the transplant due to Polyomavirus infection.Our initial experience of combined heart and kidney transplantation was favorable in selected patients with advanced heart failure and end-stage kidney disease. It requires involvement of a dedicated multispecialty team throughout all the diagnostics and treatment steps. Cardiorenal syndrome is frequent in advanced heart failure patients. A particular subset of those presents with underlying kidney disease or even prolonged dialysis-dependent acute kidney injury, in which kidney recovery after isolated heart transplantation is less probable. Combined heart and kidney transplantation has been proposed as an attractive alternative of treatment of those patients. United Network for Organ Sharing (UNOS) data has shown that the number of patients on the waiting list with this modality of transplant is progressively increasing, as well the number of combined transplants performed.Combined solid organ transplantation including the heart is infrequently performed in Brazil. Published medical literature include only anecdotal reportsWe aim to present our early experience with combined heart and kidney transplantation in Brazil.From January 2007 to December 2019, 276 patients were consecutively submitted to orthotopic heart transplantation. Among those, combined heart and kidney transplantation was performed in four patients (1.4%).Data were retrieved in part from the prospective heart transplantation and kidney transplantation registries and in part from each electronic patient’s medical record. These data were approved by the Institutional Review Board, which also approved their use for research purposes (COI 23681413.5.0000.0026) with patient consent waived. and receiving multidisciplinary team clearance. A consultation with a kidney transplantation team included clinical assessment of perfusion status, relevant hemodynamic parameters (invasive and noninvasive), detection of markers of intrinsic kidney injury, and a thorough investigation of alternative explanations for worsening renal function with renal ultrasonography and biopsy in one patient. A multidisciplinary discussion of risks and benefits aided in the decision to proceed with a combined heart-kidney transplantation. Brazilian Ministry of Health policies on combined transplantation listing and organ allocation determines that these patients must be listed as heart transplantation recipients, using the same criteria as other isolated heart transplantation recipients.All patients had documented stage D heart failure with reduced ejection fraction, and they were listed for combined heart-kidney transplantation after fulfilling specific criteriaAll patients were submitted to complement-dependent cytotoxicity crossmatch before donor acceptance. For that reason, all donors were transferred to and were supported by our hospital in order to ensure appropriate heart function at the time of organ procurement and to minimize cold ischemic times.Organ procurement was performed in the same hospital as the implantation. All local donors are routinely transferred to our hospital for procurement. Patients were routinely monitored with a pulmonary artery catheter and intraoperative transesophageal echocardiography. First, orthotopic heart transplantation with bicaval anastomosis was performed with normothermic cardiopulmonary bypass and hypothermic antegrade blood cardioplegia for myocardial protection. Just after the end of heart transplantation, with the chest closed, kidney transplantation was commenced. Induction therapy with thymoglobulin was used in all patients, and the maintenance regimen was tacrolimus, azathioprine, and prednisone.Postoperative management followed institutional protocols, which include early extubation, hemodynamic support aiming cardiac index > 2.5 L/min/m2, central venous pressure < 10 mmHg, and pulmonary wedge pressure < 10 mmHg. Diuresis was > 50 ml/hour. Cardiac function is verified with bedside transthoracic echocardiography in case of clinical suspicion or altered parameters with invasive monitoring. Follow-up was obtained through medical consultations and appropriate tests. Surveillance endomyocardial biopsies were performed weekly in the first month, then monthly in the next five months, and every six months thereafter. Diagnosis of rejection follow the International Society for Heart and Lung Transplantation classification. We have completed follow-up of all patients.2, mean systolic pulmonary artery pressure of 51.5±7.9 mmHg, mean right atrial pressure of 19±6.7 mmHg, and mean pulmonary vascular resistance of 4.5±2.4 Wood units. Patients remained on the waiting list a mean of 138±97 days, and two of them were on priority status at the time of transplantation, being inotrope dependent.Patients’ mean age was 55.7±4.4 years and three (75%) of them were males. Data is summarized in All patients were on dialysis (median of 12 months) prior to transplant. Mean serum creatinine was 4.7±2.8 mg/dl and mean glomerular filtration rate was 20.4±14.4 mL/min/m2. Etiology of kidney disease was cardiorenal syndrome in two patients, organophosphate pesticide-induced nephrotoxicity in one patient, and undetermined in the last.Two patients had had panel-reactive antibodies prior to transplant. Mean donor age was 19.7±1.2 years and three (75%) were males. The causes of death were head trauma in three (75%) and hemorrhagic cerebrovascular accident in the last. Donors did not have any important comorbidities, and only one had active infection . Mean cold ischemic times were 68.7±15.6 minutes. One patient developed severe primary graft dysfunction in the operating room because he failed to wean off cardiopulmonary bypass and required extracorporeal membrane oxygenation (ECMO). Kidney transplantation was performed with the patient on ECMO.Postoperatively, median duration of hospitalization was 52 days. Mean serum creatinine at hospital discharge was 1.4±0.5 mg/dl, mean retarded kidney graft function was 22.9±9.7 days, with an average of 23.7±2.6 sessions of post-transplant dialysis. One patient had kidney 2R acute cellular rejection two months after transplant, and active cytomegalovirus infection occurred in two patients. Mean follow-up was 34.7±17.5 months (variation 22 - 48 months). There was no death. One patient lost the kidney graft two years after the transplant due to Polyomavirus infection. All patients were in NYHA functional class I at the latest follow-up. and arrhythmia-related sudden death, being an independent predictor of transplant waitlist mortality.The present data shows a single-center initial experience on combined heart-kidney transplantation in Brazil, which is the first published experience to date. Our data relates to a population of Chagas cardiomyopathy patients with stage D heart failure refractory to medical treatment. Both noninvasive and invasive markers of disease severity were consistent with the need for heart transplantation. Chagas cardiomyopathy is associated with frequent biventricular dysfunctionConcomitant important kidney disease was determined in all patients because all were on dialysis (median of 12 months prior to transplant), among other findings. However, there were two different clinical profiles in our experience. Chronic primary kidney disease with long-term outpatient dialysis was present in patients 3 and 4. They were listed and waited at home with no signs of end-organ dysfunction. On the other hand, patients 1 and 2 presented with cardiogenic shock and end-organ dysfunction, with cardiorenal syndrome. They were initially stabilized with intravenous inotropes and developed worsening kidney function, with the need for hemodialysis. The decision to proceed with the combined transplant was driven by a combination of factors . The decision was shared by a multidisciplinary panel of specialists. One may argue that bridging these patients with durable mechanical devices would potentially reverse end-organ dysfunction, opening the possibility of an isolated heart transplant in the future. Although this strategy is standard of care in many countries, it seems complicated in Brazil due to the unavailability of devices in the Brazilian public health system. Moreover, the type of mechanical support would be potentially a biventricular assist device or total artificial heart, giving the heart failure etiology..The most important issue to be discussed is patient selection; central to a discussion of combined organ transplantation is the question of whether native renal function will improve following heart transplantation alone. Kidney transplantation can be requested at time of heart transplantation or years after; however, no consensus exists regarding indications and timing for kidney transplant. A combined heart and kidney transplantation approach for treating coexisting end-organ failure at the time of heart transplantation has shown increased survival for both dialysis-dependent patients and patients with reduced preoperative glomerular filtration rate to 37 mL/min, but there is still no consensus about the threshold below which the combined procedure would be recommended. The International Society for Heart and Lung Transplantation consensus guidelines from 2016 do list an eGFR < 30 mL/min/m2 as a relative contraindication to heart transplantation , which serves as recommendation for combined heart-kidney transplantation.However, there are no uniformly agreed upon criteria for selecting a combined organ transplant strategy over sequential or isolated organ transplant. A threshold of estimated glomerular filtration rate (eGFR) has been searched by several investigators as a guide that potentially justified combined transplantation. Previous studies recommend combined heart and kidney transplantation for patients with renal function in the interval from 33 mL/min shows that patients with a preoperative eGFR < 30 mL/min or in dialysis achieved a longer survival with combined heart-kidney transplantation compared with sequential kidney transplantation after heart transplantation. Patients who required the latter strategy are usually those who after heart transplantation develop kidney failure due to calcineurin inhibitor nephrotoxicity. The median time between heart and kidney transplant was six years. All of our patients were on preoperative dialysis and had a mean eGFR of 20.4±14.4 mL/min, which supports the indication for combined transplantation.The most recent publication from the UNOS database.Cardiorenal syndrome was the most frequent cause of kidney failure in our patients. Because of combined transplantation is infrequently performed in our country, it is important to recognize that the eligibility of patients that would potentially benefit from this strategy is underappreciated in Brazil. Concurrent allocation of dual organs in these recipients appears appropriate and this has important implications for organ allocation, particularly because it utilizes two organs in one recipient. In Brazil, patients listed for combined heart and kidney transplantation remain in the heart transplantation listing with the same criteria of allocation and prioritization organized and regulated by the Ministry of Health. There are ethical issues related to combined transplantation due to scarcity of organs for every recipient. For that reason, strict and precise indications for combined transplantation are of paramount importance, particularly because of high mortality rates observed in advanced heart failure patients on the waiting list for isolated heart transplantation. Similar debate prevails in the indication of single lung transplantation in certain pulmonary diseases that enhances the number of treated patients, as opposed to double lung transplantation improves survival on less treated patients.It is certainly a more complex group of patients in terms of disease severity, and it is more complex to perform. It requires two surgical teams that do operate in sequence and it requires though a coordinated team with prolonged operating room time. In our center, we decided to limit to local donors only in order to minimize cold ischemic times, to test for real crossmatch, and to use induction therapy with thymoglobulin as a routine. On the other hand, there is experimental evidence to suggest that the greater mass of transplanted tissue may reduce rejection rates and promote graft toleranceIn conclusion, our initial experience of combined heart and kidney transplantation was favorable in selected patients with advanced heart failure and end-stage kidney disease . It requ


Several countries reported a substantial reduction in asthma exacerbations associated with COVID-19 pandemic-related restrictions. However, it is not known if these early reported declines were short-term and if these have rebounded to pre-pandemic levels following easing of lockdown restrictions.We undertook a retrospective, cohort study of all asthma patients in a national primary care database of almost 10 million patients, Optimum Patient Care Database (OPCRD), identified from January 1, 2010, to December 31, 2015, using a previously validated algorithm. We subsequently followed the identified cohort of asthma patients from January 1, 2016, to October 3, 2021, and identified every asthma exacerbation episode with a validated algorithm. To quantify any pandemic-related change in exacerbations, we created a control time-series (mean of 2016-2019) and then compared the change in exacerbation rate in 2020-2021 over quarterly periods when compared with the control period (the pre-pandemic period). We undertook overall and stratified analyses by age group, sex, and English region.We identified 100,362 asthma patients  from across England who experienced at least one exacerbation episode . Except for the first quarter of 2020, the exacerbation rates were substantially lower (>25%) during all quarters in 2020-2021 when compared with the rates during 2016-2019 : 34.6, 44.9) in quarter-2, 2020; 46.5%  in quarter-3, 2020; 56.3%  in quarter-4, 2020; 63.2%  in quarter-1, 2021; 57.7%  in quarter-2, 2021; 53.3%  in quarter-3, 2021).There was a substantial and persistent reduction in asthma exacerbations across England over the first 18 months after the first lockdown. This is unlikely to be adequately explained by changes in health-seeking behaviour, pandemic-related healthcare service disruption, or any air-quality improvements.Asthma UK, Health Data Research UK (HDR UK), Medical Research Council (MRC), National Institute for Health Research (NIHR). We searched PubMed and medRxiv on November 21, 2021, using the query “asthma AND (exacerbation OR attack) AND (SARS-CoV-2 OR COVID-19 OR pandemic OR lockdown)” for all studies published since January 1, 2020, with no language restrictions and limiting PubMed search span to [Title/Abstract]. Of the 122 search results , after screening each study's abstract we identified 47 potentially relevant studies. We also identified two additional studies that we deemed relevant.Overall, 20 studies investigated asthma exacerbation patterns during the pandemic, and they all reported substantial reductions in exacerbation rates. Four studies used self-reported data, and 16 studies used routinely collected data. However, most of the studies covered a small geographical area, often from a single hospital and 10 studies focused on paediatric patients only. The five relatively large, country-wide studies that used routinely collected data were from Scotland and Wales , Hong Kong , and Japan  using hospital data, and from England (our previous study) and the UK  using primary care recorded data. All these relatively large sample size studies had a short follow-up with the longest one reported in our previous study (until August 2020). Even amongst all 20 studies, the follow-up time was mostly short, and they could only assess the short-term impact of the pandemic when various restrictions were freshly imposed and when there were no COVID-19 vaccinations. The only exception was a study from Dublin  that assessed the pandemic impact on asthma exacerbations until February 2021.In summary, several studies from various countries have reported a substantial reduction in asthma exacerbations that were attributed to pandemic-related restrictions in 2020. However, it was not clear if the early reported, substantial reductions were short-term and if there has been a rebound to pre-pandemic levels with easing of restrictions.To our knowledge, this is the longest and one of the largest studies to assess the impact of the pandemic on asthma exacerbations. Previous short-term studies offered various hypotheses to explain the substantial reduction in asthma exacerbations during the pandemic, such as improved air quality, change in health-seeking behaviours due to fear of COVID-19, healthcare disruption, and reduced exposure to other viruses.By demonstrating substantial and sustained reduction in asthma exacerbations over 18 months (since the first lockdown), during periods with varied pandemic-related public health measures, this analysis suggests that change in health-seeking behaviour due to fear of COVID-19, healthcare disruption and improved air quality are unlikely to explain a consistent and sustained reduction in asthma exacerbations.A substantial and sustained reduction in asthma exacerbations is possible with various primary and public health measures. Further research is required to design and develop pragmatic interventions to ensure that the low rate of asthma exacerbations can persist beyond the COVID-19 pandemic.Alt-text: Unlabelled box,Several countries reported a substantial reduction in asthma exacerbations during the on-going COVID-19 pandemic.Since the pandemic, the United Kingdom (UK) government has thrice imposed strict emergency restrictions  with the first one in March 2020.In this study, we aimed to investigate the impact of the pandemic, and the associated measures that have ranged from strict, country-wide lockdown to minimal restrictions, on asthma exacerbations over 18 months since the first national lockdown.The Optimum Patient Care (OPC) network collects anonymised clinical data from General Practitioner (GP) practices from across the UK. This dataset is fully anonymised and hosted in a dedicated data repository called the Optimum Patient Care Research Database (OPCRD). Access to OPCRD is regulated and available to bona fide researchers subject to licensing agreements and study-specific permissions.https://opcrd.co.uk/).OPCRD has been used in several epidemiological, pharmaceutical, and other observational clinical studies . The Anonymized Data Ethics and Protocol Transparency (ADEPT) Secretariat oversee the use of OPCRD and grant project-specific approvals. To be able to use the OPCRD for this project, we obtained ADEPT approval (reference number:ADEPT1020a).We designed a retrospective cohort study and identified all asthma patients through a validated algorithmThe primary outcome, computed for every week during follow-up, was the rate of asthma exacerbation. This rate was computed as the total number of episodes per 100 patient-years. An asthma exacerbation was based on the definition of American Thoracic Society (ATS)/European Respiratory Society (ERS) Task Force definition, previously validated in OPCRD.To compute the exacerbation rate, we first counted the total number of exacerbation episodes in each week, and then divided it by the number of patients in the cohort in that week. This gave us the exacerbation rate as the number of episodes per patient-week. We then converted this rate into number of episodes per 100 patient-years. We subsequently plotted the exacerbation rate (updated weekly) during the entire follow-up to visually assess any temporal trends and any impact during the pandemic. The exacerbation rate for a given week corresponds to the rate observed over the following seven days starting from a given week's beginning date.To facilitate statistical comparison between the pandemic and the pre-pandemic period, we divided the entire follow-up into yearly quarters . For each quarter, we computed the mean of the 13 weekly exacerbation rates  with 95% confidence interval . We constructed a control time-series from the quarterly exacerbation rates during the pre-pandemic period (2016-2019). The exacerbation rate in each quarter in the control time-series was equal to the mean of corresponding quarterly exacerbation rates during the pre-pandemic period . We computed the difference in mean, the 95% CI using the Welch's 2-sample t-test  and the percentage difference in the exacerbation rate between a given quarter in 2020-2021 and the corresponding rate during 2016-2019 using the control time-series.In addition to overall analysis, we carried out stratified analyses. We independently stratified our cohort by sex , age , and location . We only had access to year of birth. We approximated each patient's age by assuming them to be born mid-year (July 1). For age-based stratification, we used the age of each patient on January 1, 2016 (the start date of the follow-up period). We did not have individual-level location data. We therefore used the postcode information of each GP practice to infer location of each patient.We anticipated attrition of participants over the long follow-up period of almost six years. Possible reasons for this include patients moving out from the area, patient's asthma resolving and the patient having no further contact with the GP, and patients dying. To investigate if there was any difference between the subset of patients who remained and those who dropped out over time, we undertook additional sensitivity analysis by restricting the cohort to only those who stayed until at the last quarter during the follow-up.Lastly, we undertook additional sensitivity analysis to assess the impact of some patients in the cohort having COPD in addition to asthma. We restricted the cohort to those aged 34 or under at the start date of the follow-up. The cut-off of 34 at the start of the follow-up ensured that all patients in the restricted cohort were under 40 years at the study end date.All analyses were undertaken in R (version 3.6.2) using RStudio (version 1.4.1717). We used the tidyverse packages for data wrangling (dplyr) and plotting (ggplot2). We used the lubridate package for date manipulation, and the RODBC library to remotely connect to the OPCRD database. “STROBE” and “RECORD” were used to aid transparent reporting.The funders did not play any role in the study design, data collection, data analysis, interpretation or in the writing of this report.Out of the 9,949,387 patients in the database, we included 571,166  eligible asthma patients. There were 100,362 (17.6%) patients with at least one exacerbation episode during the follow-up period . The total follow-up period in the study was 502,669 patient-years with a mean follow-up of 5.01 years per patient  or ≥55years . The number of young patients was relatively small . Most of the young patients were 3-5 years old (appendix p.12). A small minority of patients  did not have birth year recorded in the database and were therefore excluded during age stratification.Stratified by sex, there were substantially more females  than males . A small minority of patients  did not have sex information recorded in the database and were therefore excluded during sex stratification. Stratified by region, a large proportion of patients were from East England, South East, and Yorkshire and the Humber.,When further stratified by both age and sex, there were more males than females in the younger age groups  but a substantially greater number of females than males in the older age groups . While we were unable to identify any existing previous study that reported prevalence of asthma patients amongst those who had at least one exacerbation during a specific study period, the overall pattern that we observed in our data  is corroborated by previous studies in the UKThere were 298,390 exacerbation episodes experienced by the 100,362 patients during the follow-up period. The mean exacerbation rates during the entire follow-up stratified by sex, age, and region broadly follow a similar pattern . There was a strong seasonality pattern during the pre-pandemic period, and there was a consistent and substantial reduction in exacerbation rates during the pandemic.The most common hospital-related code used in our study was “663m.” which is defined as “Asthma A&E attendance since last visit”. Due to lack of linkage with a secondary care data source , we were unable to determine with certainty if a given previous attendance to A&E due to asthma got resolved on the day of attendance or if it required hospitalisation. We have, therefore, stratified the exacerbation type by the clinical setting where it got resolved: primary care, and hospital (includes both A&E attendance and admissions). Figure S9 (appendix p.7) shows the overall exacerbation rates during the follow-up when stratified by clinical setting. Even before the pandemic, most asthma exacerbation episodes were resolved within primary care. In our dataset, 263,120 exacerbation episodes (88.2%) were resolved in primary care and 35,270 (11.8%) were resolved in hospital. It is evident that the overall asthma exacerbation trend during the follow-up is primarily driven by exacerbations that get resolved within primary care.Overall, the mean exacerbation rate was not substantially (<25%) different during the first quarter of 2020 compared with the control period (mean of 2016-2019). However, the exacerbation rates were substantially lower (> 25%) during all remaining time intervals in 2020-2021 when compared with the rates during 2016-2019  for males, and 61.0% for females . Stratified by age, the mean exacerbation rate dropped by up to 81.9% for 0-5 , 73.1% for 6-17 , 52.5% for 18-54 , and 68.2% for 55+ . Stratified by region, the mean exacerbation rate dropped by up to 67.4% for East England , 68.8% for East Midlands , 64.2% for London , 51.2% for North East , 48.8% for North West , 65.4% for South East , 71.8% for South West , 68.2% for West Midlands , and 64.4% for Yorkshire and the Humber . Stratified by whether an exacerbation episode was resolved within primary care or whether it required a hospital visit (secondary care), the change in secondary care-based exacerbation rates is small, ranging from 3.4  to -6.7  episodes per 100 patient-years. However, the reduction in exacerbations that were resolved within primary care is substantial, ranging from -51.1  to -21.2  episodes per 100 patient-years.Figures S12 and S13 (appendix p.9) plot the exacerbation rates over time when the cohort is restricted to the: 58,776 patients who stayed in the cohort until at the last quarter during the follow-up; 27,095 patients who were aged 34 or under at the start of the follow-up period. The overall pattern in these sub-cohorts during the follow-up was similar to the pattern of the entire cohort: strong seasonal pattern before the pandemic peaking in winters (December-January 2016-2019), gradually dropping and reaching a trough in the summers (May-June 2016-2019), gradually rising again from September 2016-2019, substantial reduction beginning from the first lockdown period (March 2020) and the large drop during the pandemic sustaining until the study end date of October 3, 2021. It is evident from the figures that there is no systematic difference between taking the entire cohort and restricting the cohort to only those who remained until the end of the study, or to those aged 34 or under at the start of the follow-up period.This large nationwide analysis has found substantial reductions  in asthma exacerbations over 18 months since the imposition of the first lockdown in March 2020. These reductions were observed for both males and females, all age groups, and all regions across England and all periods studied.,,In addition to our previous study suggesting a substantial, short-term reduction in asthma exacerbations at the beginning of the pandemic,9Most previous studies that used routinely collected healthcare data leveraged secondary-care data only. Consequently, these studies were only able to assess the impact of the pandemic on severe asthma exacerbations that required a hospital visit. However, the majority of UK asthma patients are treated in primary care.,,7,,,Previous studies have suggested several factors to explain the substantial reduction in asthma exacerbations during the pandemic. These included a change in care-seeking behaviour with patients more likely to avoid contacting visiting healthcare facilities due to fear of contracting COVID-19,While early studies suggested that some people might avoid seeking healthcare facilities due to fear of COVID-19,,Similarly, healthcare disruption is also unlikely to be a key factor since many pandemic-related restrictions were eased during the long follow-up, first in summers 2020, and then from July 19, 2021 after widespread vaccination coverage, in an attempt to mitigate pandemic-related disruptions.While it is not possible to ascertain the role (and extent) of any improved self-management, this could have contributed to the reduction observed since patients with chronic conditions were more likely to adhere to pandemic-related restrictions as opposed to those without any chronic conditions.,Overall, the most likely explanation for the substantial, persistent drop in exacerbation rates seen across England is reduced exposure to respiratory viruses such as rhinoviruses that are common triggers of asthma exacerbations.The key strengths of this study are the use of a large, country-wide dataset with over half a million asthma patients of whom over 100,000 developed an exacerbation, a long follow-up period (January 2016-October 2021) with 18 months during the pandemic, the use of previously validated algorithms for identifying asthma patients and ascertaining asthma exacerbation episodes, and the use of clinician-recorded, routinely collected primary care data from over 500 independent GP primary care practices with different clinical data recording systems covering a large geographic area. To our knowledge, this is the longest and one of the largest studies to assess the impact of the pandemic on asthma exacerbations. By restricting our analyses to only those who experienced at least one exacerbation episode during follow-up, we have excluded the following those: whose asthma resolved; who were earlier misdiagnosed with asthma during the cohort selection period, January 2010-December 2015; whose symptoms are so well-controlled that they never had any episode of exacerbation in the follow-up period .There are, however, six key limitations to note. First, despite being large and multi-centered, this was a descriptive study, and we cannot definitively identify causal factors that may explain the substantial reduction in exacerbation rates observed. This study has allowed us to hypothesise the likely mechanisms, but these now need further detailed investigation. Second, we were only able to access primary care dataset and any data records of patients self-referring to secondary care services were not directly accessible from hospital databases. However, we believe that any self-referred, asthma-related hospitalisation episodes that are not recorded in primary care will be rare. This is because all hospitalisations are accompanied by a discharge letter that gets sent to primary care via a NHS document system, and the majority get coded in primary care.This study provides a clear and compelling demonstration that substantial reduction in asthma exacerbations is possible without additional pharmacological interventions (beyond what is currently available). Further research is now required to design and develop pragmatic non-pharmacological interventions that could reduce exposure to respiratory viruses and promote improved self-management to ensure that the low rate of asthma exacerbations persists beyond the COVID-19 pandemic. Clinical approaches to manage asthma patients should also be reconsidered such as redesign of waiting rooms in different clinical settings, and the use of remote consultations to mitigate the risks of exposure to other respiratory viruses.AS conceived this analysis and oversaw all aspects of the study. SAS with AS and JQ designed the study. SAS undertook all the analysis and wrote the first draft of the manuscript. All authors commented critically on the manuscript and approved the final version.https://opcrd.co.uk/) subject to licensing agreement and independent evaluation of the scientific protocol. All the code used in this study will be made publicly available at GitHub (https://github.com/syedahmar/) and the associated metadata will also be made available via BREATHE.The data used in this study can be accessed from OPCRD (AS is a member of the Scottish Government Chief Medical Officer's COVID-19 Advisory Group and its Standing Committee on Pandemics, and NERVTAG's Risk Stratification Subgroup. All other authors declare no conflict of interest related to this work.


Pheochromocytoma is a rare catecholamine-secreting tumor. Tumor resection remains a high-risk procedure due to intraoperative hemodynamic instability nowadays, which may lead to myocardial injury. We aimed to determine the incidence and associated risk factors for myocardial injury after laparoscopic adrenalectomy for pheochromocytoma.th percentile upper reference limit due to cardiac ischemic causes.Adult patients  who underwent elective laparoscopic adrenalectomy for pheochromocytoma under general anesthesia between January 31, 2013 and January 31, 2020 were included in this observational, retrospective, single-center, cohort study. Blood troponin I levels were measured before and during the first 2 days after surgery. Myocardial injury was defined as an elevated troponin I level exceeding the 99P=0.013), intraoperative heart rate >115 bpm , intraoperative systolic blood pressure >210 mmHg , and perioperative decrease in hemoglobin level were associated with an increased risk of myocardial injury. For the cumulative duration of dichotomized intraoperative hemodynamics, multivariable analysis showed that intraoperative heart rate >115 bpm for >1 minute  and systolic blood pressure >210 mmHg for >1 minute  were associated with an increased risk of myocardial injury. The risk of myocardial injury progressively increased with a longer cumulative duration of intraoperative tachycardia and hypertension.Myocardial injury occurred in 42/350 patients . In multivariable analysis , previous ischemic heart disease or stroke (5.04 [1.40–18.08]; There is a high incidence of myocardial injury after laparoscopic adrenalectomy for pheochromocytoma. The identified risk factors may assist physicians in detecting high-risk patients and providing guidance for intraoperative hemodynamics and perioperative hemoglobin management. Pheochromocytomas are rare catecholamine-secreting tumors arising from adrenomedullary chromaffin cells, with an overall incidence of 0.18 to 0.66 per 100,000 person-years in the general population  and 0.2%Postoperative myocardial injury, defined as troponin elevation due to ischemic etiologies, has recently been identified as a crucial and undetected adverse cardiovascular outcome following non-cardiac surgeries . TroponiThe manuscript was prepared according to the Strengthening the Reporting of Observational Studies in Epidemiology statement . This waFor preoperative management, all patients received non-selected α-blockade therapy for more than seven days. Phenoxybenzamine was administered and the dose was titrated to maintain the BP < 140/90 mm Hg. The β-blocker was added when necessary to maintain the HR < 90 bpm after α-blockade had been achieved. Treatment also included a high-sodium diet and fluid intake to reverse catecholamine-induced blood volume contraction before surgery to prevent severe hypotension after tumor removal.For anesthesia implement and critical care, all patients received general anesthesia and an arterial line for invasive BP monitoring before general anesthesia implement. Central venous access was retained after anesthesia induction. Arterial BP and HR measurements were recorded automatically by the monitor every 10 seconds. During surgery, hypertensive and hypotensive episodes were treated at the anesthesiologists’ discretion. Generally, vasodilators were administered when systolic blood pressure (SBP) was higher than 160 mmHg and vasopressors were administered when SBP was lower than 90 mmHg. Hypertension was treated with vasodilators, such as nitroprusside infusion and phentolamine bolus for target BP response. Hypotension was treated with aggressive administration of intravenous fluid, discontinuation of vasodilator infusions, and administration of rapidly acting vasopressors, including phenylephrine, norepinephrine, and epinephrine. Esmolol was administered for tachycardia control. After surgery, all patients were routinely transferred to the intensive care unit before admission to the general ward. Blood troponin I levels were measured before and during the first 2 days after surgery. For patients with increased troponin I level, a cardiology specialist was consulted initially. At the same time, a 12-lead electrocardiogram(ECG) and bedside point-of-care echocardiography were performed to identify evidence of myocardial infarction. The troponin I test was repeated every 2–6 hours following the cardiology specialists’ consultation until it returned to normal levels. Myocardial infarction diagnoses were centrally adjudicated and required both, the increased troponin I levels and at least one symptom (chest pain or shortness of breath) or sign . Once the patient was diagnosed with myocardial infarction, cardiovascular treatment was initiated immediately, including antiplatelet therapy, anticoagulation, catheterization, and angioplasty.Preoperative, intraoperative and postoperative data were extracted from electronic medical records. Preoperative data included age, sex, body mass index(BMI), American Society of Anesthesiology(ASA) physical status, smoking history, alcohol use, diabetes mellitus, hypertension, previous ischemic heart disease or stroke, previous congestive heart failure, preoperative hemoglobin, troponin I and creatine levels, 24-hour urinary catecholamine level, tumor size and location, preoperative medical treatment, as well as noninvasive BP and HR before surgery. Ischemic heart disease refers to a history of myocardial infarction, positive exercise test, current complaint of ischemic chest pain or nitrate use, or ECG with pathological Q waves; it also includes patients with a history of previous coronary bypass surgery or angioplasty. Stroke refers to the ischemic stroke (thrombotic/embolic/systemic hypoperfusion) or hemorrhagic stroke . Intraoperative data included hemodynamic parameters , surgical approach and duration, estimated blood loss, red blood cell (RBC) and fresh frozen plasma (FFP) transfusion. Postoperative data included postoperative hemoglobin and troponin I levels of the first 2 days after surgery, postoperative hypotension requiring vasopressor infusion, length of stay, in-hospital complications and mortality.Artifacts of intraoperative hemodynamic parameters  were removed using published rules , in the th percentile upper reference limit due to cardiac ischemic causes, according to the VISION study  to explore myocardial injury without intraoperative hemodynamics. Variables potentially related to the risk of myocardial injury were also included. These included age, sex, BMI, ASA physical status, smoking history, alcohol use, diabetes mellitus, hypertension, previous ischemic heart disease or stroke, previous congestive heart failure, preoperative creatine, preoperative 24-hour urinary catecholamine elevation , multiples of the normal reference upper limit value , tumor location, tumor maximum diameter, preoperative medications , duration of alpha blockade, daily dose of phenoxybenzamine, hemodynamic variables before surgery , surgical approach and duration, RBC and FFP transfusion, perioperative decrease in hemoglobin, and postoperative hypotension requiring vasopressor infusion. Next, we estimated the potential risk factors for Model 1 following the addition of each of the five previously established HR thresholds (Model 2) and SBP thresholds (Model 3). Finally, to explore the cumulative duration of the dichotomized intraoperative hemodynamics above, we assessed the relationships between myocardial injury and the aforementioned variables for a cumulative time of 1, 5, 10, 15, and 20 minutes (Model 4).Continuous numerical data are presented as mean ± standard deviation or median (interquartile range), and categorical data as frequencies and percentages. Univariable analysis was performed using the Student’s P-value <0.05 was considered statistically significant.Considering the total number of myocardial injuries (n=42) in our study and to avoid overfitting the model, four variables were chosen for multivariable analysis based on previous findings and clinical constraints. The collinearity between factors was assessed using the variance inflation factor. A variance inflation factor >5 was used to define significant collinearity . All sta2), and most patients were non-smokers (82.0%), with no alcohol use (81.9%) and ASA physical status 2–3 (97.4%). Although less than half of the patients had hypertension before surgery (44.9%), all patient received preoperative medical preparation, including alpha-adrenergic blockade alone (66.0%) or combination with beta blockade (24.9%), and achieved the target hemodynamics. Other comorbidities included diabetes mellitus (18.3%), previous ischemic heart disease or stroke (7.7%), and previous congestive heart failure (6.0%). The mean maximum tumor diameter was 4.8 cm, and the 24-hour urinary norepinephrine level was particularly elevated in 51.1% patients. More than 90% patients with unilateral tumors underwent successful laparoscopic resection, and 13 patients (3.7%) were converted to laparotomy during surgery. Intraoperative established blood loss was minimal (median [interquartile range]) (100 [50–300] mL). However, the postoperative decrease in hemoglobin level was significant (mean ± standard deviation) (1.8 ± 1.1 g/dL). Prolonged hypotension requiring vasopressors infusion occurred in over half of the patients (58.9%) before they were transferred to the intensive care unit.A total of 350 patients who underwent elective laparoscopic adrenalectomy for pheochromocytoma were included finally. Patients’ characteristics, medical history, and perioperative data are shown in The outcomes up to hospital discharge are presented in The incidence of transient tachycardia and hypertension was high in all patients, with approximately 90% patients having tachycardia (HR >100 bpm) and one-third having severe hypertension (SBP >210 mmHg). Furthermore, the incidence of hypertension and tachycardia was higher in the myocardial injury group and the difference increased progressively with higher BP and HR values. The dichotomized intraoperative hemodynamics in both groups are presented in P<0.017). In the multivariable analysis in Model 3, in addition to the above three risk factors, severe hypertension (SBP >210 mmHg) was associated with an increased risk of myocardial injury . There was a trend toward an increased risk of myocardial injury as the highest intraoperative HR and SBP values increased , tachycardia (HR >115 bpm), and perioperative decrease in hemoglobin level were associated with postoperative myocardial injury.The incidence of myocardial injury (12.0%) in our study was higher than that in previously reported non-cardiac abdominal surgeries , 30.HoweIn this study, we observed that previous ischemic heart disease or stroke were significantly associated with postoperative myocardial injury, consistent with many proposed clinical cardiac risk assessment tools –35. The Preoperative risk factors, such as patient characteristics and comorbidities, are stronger predictors of adverse cardiovascular outcomes than intraoperative blood pressure . NeverthA perioperative decrease in hemoglobin level reduced myocardial oxygen supply, which was associated with myocardial injury in our study. Massive intraoperative hemorrhage is usually the main reason for the significant decrease in perioperative hemoglobin level. In the POISE  trial, severe bleeding (requiring ≥2 units of RBC) was a significant predictor of perioperative myocardial infarction , which was also confirmed by the subsequent POISE-2 trial . HoweverThe current study included a relatively large sample size for rare tumors. However, there are some limitations. First, myocardial injury was defined by the peak troponin I level, which may underestimate the occurrence of myocardial injury compared with fourth- and fifth-generation high-sensitivity troponin T . Second,In conclusion, we identified the incidence and perioperative risk factors for myocardial injury after laparoscopic adrenalectomy for pheochromocytoma. Perioperative monitoring of troponin I should be performed before surgery and during the first 2 days for this high-risk operation. Our results suggest that extra attention should be paid to patients with preexisting ischemic heart disease or stroke, severe intraoperative hypertension and tachycardia, and a significant perioperative decrease in hemoglobin levels. Further studies are required to confirm our results and explore the predictors of myocardial injury in this population.α blockade (day), phenoxybenzamine (mg/day), hemodynamic variables the day preceding surgery, surgical duration (min), blood loss (mL), and hemoglobin drop were considered as constant variables in the multivariable models. * P<0.05, $ P<0.01. Full multivariable models are presented in the Supplemental Digital Content  physical status, smoking history, alcohol use, diabetes, hypertension, previous ischemic heart disease or stroke, previous congestive heart failure, preoperative 24-h urinary catecholamine elevation ,tumor location, preoperative medications , α blockade + β blockade, α blockade + β blockade + CCB), surgical approach, red blood cells transfusion, fresh frozen plasma transfusion, postoperative hypotension requiring vasopressors were considered as categorical variables, and age, body mass index, preoperative creatine, multiple of the normal reference upper limit value , maximum tumor diameter, duration of  Content S15.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.LL contributed to the study design, data collection, statistical analysis, and writing of the original draft. QS contributed to data collection and review and editing. CY and LP contributed to the study design. YZ contributed to the statistical analysis and review and editing. LX and YH contributed to the conception, study design, interpretation of the data, and review and editing. All authors read and approved the final manuscript. All authors contributed to the article and approved the submitted version.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.The authors thank Dr. Penghao Liu of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China, for his help with figure preparation.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Blood pressure (BP) exhibits seasonal variations, with peaks reported in winter. However, the association between seasonal variations and blood pressure variability in patients with new-onset essential hypertension is not fully understood. This study evaluated the potential association of seasonal variations with new-onset essential hypertension.This retrospective observational study recruited a total of 440 consecutive patients with new-onset essential hypertension who underwent 24-h ambulatory electrocardiograph (ECG) and BP measurement at our department between January 2019 and December 2019. Demographic and baseline clinical data including BP variability, heart rate variability, and blood tests were retrieved. Multivariate linear regression analysis was performed to identify factors independently associated with mean BP and BP variability.P < 0.05 for all). Multivariate linear regression analysis showed that winter was the influencing factor of 24-h standard deviation of SBP , 24-h standard deviation of DBP , 24-h SBP coefficient of variation , and 24-h DBP coefficient of variation  in hypertensive patients.Among the 440 patients recruited, 93 cases were admitted in spring, 72 in summer, 151 in autumn, and 124 in winter. Univariate analysis revealed that systolic BP (SBP), diastolic BP (DBP), high-sensitivity C-reactive protein, SBP drop rate, DBP drop rate, 24-h standard deviation of SBP, 24-h standard deviation of DBP, 24-h SBP coefficient of variation, and 24-h DBP coefficient of variation were associated with patients admitted in winter (Seasonal variations are closely associated with BP variability in patients with new-onset essential hypertension. Our study provides insight into the underlying pathogenesis of new-onset essential hypertension. Essential hypertension, also known as primary hypertension, is the most common risk factor for cardiovascular diseases , 2. TherPrevious studies have shown that cardiovascular risk can be appropriately managed by monitoring BP and seasonal changes , 8. Of nThis retrospective observational study recruited 440 consecutive patients with a first diagnosis of essential hypertension who were scheduled to receive 24-h ambulatory electrocardiograph (ECG) and BP measurement at the People's Hospital of Xuancheng City between January 2019 and December 2019. These patients included 93 who were admitted in spring, 72 in summer, 151 in autumn, and 124 in winter. Diagnostic criteria of essential hypertension conformed to criteria recently described in clinical methodology: BP measured at home three times on different days with a systolic BP (SBP) > 140 mmHg or diastolic BP (DBP) > 90 mmHg . PatientAll patients underwent 24-h ambulatory ECG and BP monitoring  upon admission to the Department of Cardiology. 24-h ambulatory BP monitoring was performed using a cuff-monitor. BP was measured every 25 min during the day (between 08:00 and 22:00) and every 60 min during the night (between 22:00 and 08:00 the next morning) using a cuff size that fit the individual’s arm circumference as previously described . Only rehttp://ah.cma.gov.cn/). Smoking was defined as current smoker. Educational qualifications were classified as illiterate, primary school, middle school, high school, specific college course, or above.The date of 24-h ambulatory BP monitoring was used to define the seasons as follows: spring: March, April, May; summer: June, July, August; autumn: September, October, November; and winter: December, January, February . Data on2) test was used to analyze the differences in categorical variables between groups, and analysis of variance (ANOVA) was used for comparisons of data among multiple groups. The Mann–Whitney U test or Kruskal–Wallis variance analysis was used for non-normally distributed data between groups. The multivariate linear regression analysis was conducted with 24-h average SBP, 24-h average DBP, 24-h standard deviation of SBP, 24-h standard deviation of DBP, 24-h SBP coefficient of variation, or 24-h DBP coefficient of variation as the dependent variable, and the variables that were statistically significant in the univariate analysis were considered independent variables. Multiple linear regression analysis was used to study the association of seasonal variations with mean BP levels and BP coefficient of variation. A P-value less than 0.05 was considered statistically significant. All statistical analyses were performed using SPSS23 ( IBM).Normally distributed continuous variables are presented as mean ± standard deviation (SD), and medians and interquartile ranges (IQRs) are otherwise presented. Categorical variables are presented as percentages. A chi-square (χP < 0.001), higher clinic DBP (P < 0.001), higher high-sensitivity C-reactive protein (hs-CRP) (P = 0.003), lower maximum temperature (P < 0.001), lower minimum temperature (P < 0.001), lower average temperature (P < 0.001), and lower mean precipitation.A total of 440 patients were registered in this study. The patients were divided into four groups according to the dates of ECG and BP measurements: 93 in spring, 72 in summer, 151 in autumn, and 124 in winter. The demographic and baseline clinical characteristics and biochemical parameters of patients in these four groups are presented in Table P < 0.05; Table P < 0.05). Heart rate, mean daytime heart rate, LF, and HF were higher in summer and winter than in spring and autumn . The winter group had the highest SBP drop rate, DBP drop rate, 24-h SBP standard deviation, 24-h DBP standard deviation, 24-h SBP coefficient of variation, and 24-h SBP coefficient of variation among the four groups (all P < 0.05; (Table P < 0.05; Table The demographic and baseline clinic characteristics and laboratory data of patients based on 24-h average SBP are shown in Table P < 0.05; Table P < 0.05; Table The demographic and clinic characteristics and laboratory data of patients based on 24-h average DBP are shown in Table P < 0.05; Table The demographic and clinic characteristics and laboratory data of patients based on 24-h standard deviation of SBP are presented in Table P < 0.05; Table P < 0.05; Table The demographic and clinical characteristics and laboratory data of patients based on 24-h standard deviation of DBP are shown in Table P < 0.05; Table P < 0.05; Table The demographic and clinical characteristics and laboratory data of patients based on 24-h SBP coefficient of variation are presented in Table P < 0.05; Table P < 0.05; Table The demographic and clinical characteristics and laboratory data of patients based on 24-h DBP coefficient of variation are shown in Table In this retrospective observational cohort study of patients with a first diagnosis of essential hypertension, we found that SBP, DBP, hs-CRP, SBP drop rate, DBP drop rate, 24-h standard deviation of SBP, 24-h standard deviation of DBP, 24-h SBP coefficient of variation, and 24-h DBP coefficient of variation were associated with new-onset essential hypertension in patients admitted in winter. It is noteworthy that those in the winter group had the highest 24-h standard deviation of SBP, 24-h standard deviation of DBP, 24-h SBP coefficient of variation, and 24-h DBP coefficient of variation.The significant effects of seasonal changes on cardiovascular diseases, including hypertension, have been well documented. In particular, BP has been reported to be higher in winter –19. WithHypertension is a multi-factorial chronic inflammatory disease, and a tight link between atherosclerosis and inflammation has emerged , 26. TheSeasonal BP variations are a global phenomenon that affect both sexes, all age groups, normotensive individuals, and untreated and treated hypertensive patients . A previFirst, our work was a retrospective observational study with a relatively small sample size, and thus there could be selection bias in our study. Second, our results might have been influenced by other environmental factors including low atmospheric air pressure, high wind velocity, shorter sunshine duration, and air pollution. Although we chose to focus on environmental temperature in the present study, we cannot rule out the potential effects of other factors on the association between environmental temperature and BP fluctuations observed in this study. Third, all patients were divided into four groups based on the date of examination. Therefore, we did not account for individual differences in the current study. However, age, sex, and cardiovascular risk factors were not significantly different between these groups. Five, 24-h-weighted indices of BP variability were not analyzed , becauseWinter was independently associated with the highest 24-h standard deviations of SBP, 24-h standard deviations of DBP, 24-h SBP coefficient of variation, and 24-h DBP coefficient of variation. It is important to integrate seasonal variations into clinical practice to make appropriate prevention and management decisions of new-onset essential hypertension.


Emergency department (ED) visits for high blood pressure are increasing in frequency. We aimed to map those patients’ trajectory, from referral sources to the type of care received at the ED to anticipated actions for future high blood pressure concerns, and to better understand their reasons for consulting the ED for high blood pressure values.Between 2018 and 2020, patients who presented to the Montreal Heart Institute’s ED for elevated blood pressure were recruited in a prospective observational study including a post hoc structured telephone interview and medical chart review. Five possible referral sources were predetermined. We provided proportions and 95% confidence intervals.A total of 100 patients were recruited . A majority  possessed a home blood pressure device, among which 46% (95% CI 36–56%) remembered receiving advice for its use. The main referral sources for high blood pressure to the ED were self-reference , advice of a lay person  or a nurse . Mainly, patients reported being concerned by concomitant symptoms or experiencing acute medical consequences , having followed the recommendation of a third party , or having concerns about their medication . Two weeks following their ED visits, consulting ED remained the main choice for future concerns about high blood pressure for 27% of participants. When specifically asked if they would return to the ED for elevated blood pressure, 73% (95% CI 64–83%) said yes.Most patients who consulted the ED for elevated blood pressure values were self-referred. More can be done to promote blood pressure education, effective use of personal blood pressure devices, and recommendations for patients and health professionals when confronted with high blood pressure results.The online version contains supplementary material available at 10.1007/s43678-022-00307-y. Hypertension is managed by primary healthcare providers. While literature does not support the emergency department (ED) as the optimal place for evaluation and treatment of elevated blood pressure , 2, ED vwarrant a timely appointment with a primary care provider” and that “patients with elevated readings who are experiencing symptoms of a heart attack or stroke should seek immediate medical assessment.” [Many people can measure their blood pressure using a home or pharmacy device. Clinical benefits include blood pressure measurement under less stressful circumstances (“non-white coat”) and optimizing antihypertensive adjustments . Nonethessment.” . AwareneThis study’s objective was to describe the referral sources and reasons of patients visiting the ED for elevated blood pressure. We also verified ownership of a home blood pressure device and the ED care received.This prospective observational cohort study was conducted from October 2018 to January 2020 at the Montreal Heart Institute (MHI)’s ED. The MHI’s ED is an open-access ED mainly devoted to cardiac emergencies with an annual census of 18,000 patients. The project was approved by the MHI’s Research and Development Ethics Board.The target population was adults presenting to the ED with elevated blood pressure values as their chief complaint, as evaluated by the Canadian Triage and Acuity Scale (CTAS). An ED nurse or physician asked those patients if they agreed to be informed about this study while being evaluated in the ED. Then the research team called patients who accepted within two weeks following their ED visit to obtain consent to participate. After obtaining the consent, we conducted a structured interview (see Appendix A). Two team members independently categorized the respondents’ answers according to predetermined categories. Participants’ medical records were reviewed to gather sociodemographic and medical information, blood pressure values at the ED triage and discharge, healthcare services received, and presence of hypertensive emergency diagnosis.This study’s main objective was to identify referral sources of patients presenting to the ED for elevated blood pressure values. Five referral sources were predetermined: (1) self-referral; (2) lay person; (3) pharmacist; (4) nurse; or (5) physician. We also described participants’ main reasons for consulting the ED for high blood pressure, the proportion of ownership of home blood pressure devices and the type of care received.Descriptive statistics were reported for continuous variables, while frequencies and percentages were presented for categorical variables. The 95% exact or Wald confidence intervals (CI) were provided for proportions. Assuming an expected proportion up to 50% of one of the five referral sources, a sample size of 100 patients would allow the precision of ± 10% for the proportion using a two-sided 95% CI. Analyses were conducted using SAS software, version 9.4 .The study included 100 patients  (See Appendix B for participants’ inclusion flowchart and C for patients’ characteristics). A majority  possessed a home blood pressure device, among which 46% (95% CI 36–56%) remembered receiving advice for its use. When asked ‘Do you know what an abnormal blood pressure value is?’, 89% (95% CI 82–96%) answered positively, reporting median blood pressure values of 140/90 as abnormal. Almost all patients  stated having a family physician, with 61% (95% CI 50–72%) reporting having access if they had a new health concern.Table All patients received a routine electrocardiogram (ECG), a procedure done on every patient seen at the MHI’s ED for general complaints, 47% (95% CI 37–57%) received blood tests, and 5% (95% CI 1–9%) underwent further medical imaging procedures. Eight patients  received oral antihypertensive medication, and none required intravenous treatment. Nearly 1 in 4 participants  had their current prescription adjusted or received an additional prescription for antihypertensive medication. One  was admitted to the short stay unit. No patients received a hypertensive emergency diagnosis, and none of them were admitted to the ward. See Appendix D for the ED care received.When asked, ‘If you have an elevated blood pressure measurement again, what are you going to do?’ the main answers were: returning to the ED , consulting a family doctor/clinic , and using relaxation/stress management strategies . When specifically asked if they would return to the ED for elevated blood pressure, 73% (95% CI 64–83%) said yes.Although a large Canadian study  exploredThe fear of experiencing an acute medical condition and the interpretation of concurrent symptoms as significant drove participants to visit the ED for their high blood pressure values. Third parties played a major role, inciting a third of these visits. This finding is consistent with other work showing that non-healthcare professionals, particularly family members, play an important role in patients’ decision-making process . Also, wResults should be interpreted cautiously considering the following limits. Participants were contacted on average 14 days following their visit, which may have induced a recall bias. To be included in the study, patients were required to answer our calls during working hours. Results may not generalize to daytime workers and may underrepresent hospitalized/deceased patients. Information about the study and subsequent recruiting being at the discretion of the ED physician/nurse may have introduced a selection bias. Although we cannot be sure that all the patients with a main chief complaint of high blood pressure were proposed for the project, all patients who agreed were contacted by the research team, and the 100 patients included were those who were reached and accepted to be involved. Furthermore, we cannot provide data about those who refused to participate or were not reachable. Finally, because of our centre’s specificity, our results may not be generalizable to other centres.Both patients and their relatives should be targeted for blood pressure education. Guidelines recommend blood pressure self-monitoring , 10, impMost patients who consulted the ED for elevated blood pressure values were self-referred and discharged. More can be done to promote blood pressure education, effective use of personal blood pressure devices and patient and health professional’s decisions when confronted with high blood pressure results.Supplementary file1 (DOCX 77 KB)Below is the link to the electronic supplementary material.


Neutrophil gelatinase-associated lipocalin (NGAL) is not only a bone-derived factor involved in metabolism, but also a biomarker of kidney disease and cardiovascular pathophysiology. We conducted this cross-sectional observational study to explore relationships between plasma NGAL and thoracic aorta calcification (TAC) in maintenance hemodialysis (MHD) patients with and without diabetes.Plasma NGAL was measured by ELISA, TAC was evaluated via computed tomography scan using a 3D quantification method or chest radiography aortic arch calcification score. Spearman correlation, Logistic regression and Partial correlation analysis were used to describe the correlations between NGAL and TAC.P = 0.026). In MHD patients without diabetes, lg (NGAL) was positively correlated with ARC value analyzed by Spearman correlation; for partial correlation analysis, lg (NGAL) was positively correlated with ARC value, after adjusting for age and sex , adjusting for age, sex and CHD , adjusting for age, sex, CHD and Alb , or adjusting for age, sex, CHD, Alb, and dialyzer membrane (polysulfone) ; however, when adjusting for age, sex, CHD, Alb and Ca, the correlation between lg (NGAL) and ARC value disappeared. Positive correlation were found between NGAL and Ca , Ca and ACR  in Spearman coefficient analysis.Plasma NGAL levels were lower in MHD patients with diabetes compared to those without diabetes  vs 56.78 ng/mL, There were positive correlations among plasma NGAL, serum Ca and ARC in MHD patients without diabetes; which suggests that NGAL is possibly a participant in cardiovascular calcification, in non-diabetic MHD.The online version contains supplementary material available at 10.1186/s12882-022-02773-z. NGAL, also known as 24p3 or lipocalin2, is a 25-kDa secretory protein, which has been found to be involved in numerous functions such as bacteriostasis, iron trafficking, metabolic regulation, chemotaxis, differentiation, proliferation and so on –4. UnderStable adult MHD patients with available plasma samples and chest radiography or computed tomography (CT) in our center from July 2019 to December 2020 were included in the cross-sectional observational study. Inclusion criteria were age ≥ 18 years and underwent MHD for at least 3 months; exclusion criteria were Kt/V < 1.2, hospitalization within 3 months before enrollment, cancer, active inflammation, or high serum C-reactive protein. This study was approved by the Ethics Committee of the First Affiliated Hospital of Shandong First Medical University, and all subjects gave their informed consent.Demographic and clinical characteristics were collected from medical records as we have described before . In detaBlood samples were collected and detected as previously described . Blood sThoracic aorta calcification (TAC) was evaluated via chest computed tomography (CT) or routine chest radiography –22. ThorP-value of less than 0.05 was considered as statistically significant. All statistical analyses were performed using SPSS 20.0 .Categorical data are presented as frequencies and percentages. Continuous variables are expressed as mean ± standard deviation (SD) for normally distributed variables and as median (interquartile range [IQR]) for variables with skewed distribution. Patients were subsequently divided into 2 groups according to comorbid diabetes or not for subgroup analysis. Differences between patients with and without diabetes were assessed using the t test, Mann–Whitney U test or Chi-square analysis, as appropriate. Spearman correlation coefficients, Logistic regression analyses and Partial correlation analysis were used to describe the correlations between NGAL and TAC. All statistical tests were two-sided, a A total of 62 stable adult MHD patients were finally included in the cross-sectional observational study in Table . All patP = 0.001); and with shorter vintage  vs 40.27 months, P = 0.007), higher systolic blood pressure (SBP) , lower diastolic blood pressure (DBP) , lower plasma NGAL vs 56.78 ng/mL, P = 0.026), lower Ca vs 2.35  mmol/L, P = 0.001), lower P  vs 1.97 mmol/L, P = 0.039), lower iPTH  vs 745.60pg/mL, P < 0.001), lower ALP vs 110.00U/L, P = 0.019), lower Cr vs 884.00 38.00) P < 0.001), lower Alb vs 42.1 g/L, P = 0.005), higher WBC vs5.11 × 10^9/L, P = 0.025). In terms of the application of medicine, lesser proportion of patients with diabetes taking calcium , sevelamer(3.7% vs 42.9%), active vitamin D, while larger proportion of them taking statins. All estimated TAC parameters incidences (Table Characteristics of study participants are shown in Table P = 0.028), no correlations were found between lg (NGAL) and other TAC parameters. Age, sex and positive factors calculated by univariable logistic regression analyses , adjusting for CHD , or adjusting for active vitamin D ; however, when adjusting for Ca or vintage, the correlation between lg (NGAL) and ARC disappeared.Univariable logistic regression analyses showed positive correlations between lg (NGAL) and ARC (Table n = 21), lg (NGAL) were positively correlated with ARC value ; no other correlations were found in total group or subgroups. Spearman correlation analysis between ARC value and all demographic, clinical characters were further performed in without diabetes group , Ca (mmol/L), Alb(g/L), dalyzer membrane (polysulfone). Age, sex and all confounders were employed in partial correlation analysis in patients without diabetes , adjusting for age, sex and CHD, adjusting for age, sex, CHD and Alb, or adjusting for age, sex, CHD, Alb, and dialyzer membrane (polysulfone); however, when adjusting for age, sex, CHD, Alb, and Ca, the correlation between lg (NGAL) and ARC value disappeared. Scatter diagrams and Spearman coefficient are shown in Fig. R = 0.644, P < 0.001), Ca and ARC, NGAL and ACR.Spearman correlation analysis between lg (NGAL) and TAC parameter values are depicted in Table Cardiovascular calcification is a common and refractory complication of MHD patients, and is closely related to the high cardiovascular morbidity and mortality , 23. In In physiological condition, NGAL was once thought to be secreted mainly by adipose tissue; however recent study showed that it is “expressed by osteoblasts, at levels that are at least tenfold higher in osteoblasts than in white adipose tissue or other organs” . In pathAbove all, the major finding of our study is that there were positive correlations among plasma NGAL, serum Ca and ARC in MHD patients without diabetes; which suggests that NGAL is possibly a participant in cardiovascular calcification under MHD condition. However, this is a cross-sectional observational study. Small sample size and no follow-up observations of cardiovascular event or mortality are limitations of this study and also the direction of future research.There were positive correlations among plasma NGAL, serum Ca and ARC in MHD patients without diabetes; which suggests that NGAL is possibly a participant in cardiovascular calcification, in non-diabetic MHD.Additional file 1 Supplemental Table 1. Univariable logistic regression analyses between aortic root calcium (ARC) and characters of all MHD patients (n = 43) MHD maintenance hemodialysis, SBP systolic blood pressure, DBP diastolic blood pressure, CHD Coronary heart disease, NGAL neutrophil gelatinase-associated lipocalin, Ca calcium, P phosphate, iPTH intact parathyroid hormone, ALP alkaline phosphatase, K potassium, HCO3- carbonate ion, BUN blood urea nitrogen, Cr creatinine, Alb albumin, LDL low density lipoprotein, TG triglyceride, SF serum ferritin; Hb hemoglobin, WBC white blood cells, PLT platelet, HD hemodialysis, HFD high-flux hemodialysis, HDF hemodiafiltration, CTA cellulose triacetate, PS polysulfone, PMMA polymethylmethacrylate. Supplemental Table 2. Spearman coefficients between aortic root calcium (ARC) and characters of MHD patients without diabetes (n = 21) MHD maintenance hemodialysis, SBP systolic blood pressure, DBP diastolic blood pressure, CHD Coronary heart disease, NGAL neutrophil gelatinase-associated lipocalin, Ca calcium, P phosphate, iPTH intact parathyroid hormone, ALP alkaline phosphatase, K potassium, HCO3- carbonate ion, BUN blood urea nitrogen, Cr creatinine, Alb albumin, LDL low density lipoprotein, TG triglyceride, SF serum ferritin; Hb hemoglobin, WBC white blood cells, PLT platelet, HD hemodialysis, HFD high-flux hemodialysis, HDF hemodiafiltration, CTA cellulose triacetate, PS polysulfone, PMMA polymethylmethacrylate.