Besides, the experimental group had evidently lower systolic blood flow velocity (Vs), diastolic blood flow velocity (Vd), and mean blood flow velocity (Vm) and evidently higher pulsatility index (PI) (p < 0.05). The levels of S100 and NSE in the experimental group increased significantly, and the level of BNDF decreased significantly (p < 0.05). In patients with hypertensive cerebrovascular disease, the level of ADPN declines; the levels of hs-CRP and sICAM-1 rise; the incidence rate of cerebrovascular complications is elevated; and there are changes in the blood lipid, cerebrovascular hemodynamic, and neurological indexes, thereby further promoting the occurrence and development of hypertensive cerebrovascular disease.The study is aimed at studying the association between the levels of serum adiponectin (ADPN), high-sensitivity C-reactive protein (hs-CRP), and soluble intercellular adhesion molecule-1 (sICAM-1) and hypertensive cerebrovascular complications. 50 patients with hypertensive cerebrovascular disease treated in Gansu Provincial Hospital from December 2016 to December 2018 were selected as the experimental group, and 50 normal people who underwent physical examination were selected as the control group. The blood pressure, heart rate, and the complications were recorded, and the serum blood lipid indexes were detected. Moreover, the content of serum ADPN, hs-CRP, and sICAM-1; the neurological indexes; brain-derived neurotrophic factor (BNDF); and neurone-specific enolase (NSE) were also determined using ELISA. The content of aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), and serum creatinine (SCR) in the experimental group was significantly higher than that in control group ( Cardiovascular disease has become an important cause of death and disability with age. The deaths caused by cardiovascular disease account for more than 20% in the elderly in Western Europe and North America. Cardiovascular disease may be a more horrible disease than death for the elderly. Hypertension is a major risk factor for stroke, and the incidence rate of atherosclerosis cerebral infarction in patients with hypertension is about 4 times than that in patients with normal blood pressure . The corAdiponectin (ADPN) is a kind of recently discovered adipocytokine produced and secreted by adipose tissues . StudiesIn the present study, patients with hypertensive cerebrovascular disease and normal people receiving physical examination were collected as experimental subjects. Then, venous blood was drawn to detect the serum routine biochemical indexes of hepatic and renal function, blood pressure and heart rate were measured in each group, and blood lipid indexes were detected. Moreover, the content of serum ADPN, hs-CRP, and sICAM-1 was determined using enzyme-linked immunosorbent assay (ELISA); the hemodynamic indexes were detected; and the neurological indexes of serum brain-derived neurotrophic factor (BNDF) and neurone-specific enolase (NSE) were also determined using ELISA, hoping to provide theoretical and experimental basis for the prevention and treatment of hypertensive cerebrovascular disease.A total of 50 patients with hypertensive cerebrovascular disease treated in Gansu Provincial Hospital from December 2016 to December 2018 were selected as the experimental group. In addition, 50 people with normal physical examination were selected as the control group, and they all signed the informed consent form. Inclusion criteria are as follows: subjects meeting the diagnostic criteria for hypertension in the Hypertension Prevention and Treatment Guideline, those who volunteered to participate in the study and signed the informed consent, and those receiving no treatment previously. Exclusion criteria are as follows: diabetic patients, those with secondary infection + severe hepatic and renal dysfunction, or those with acute myocardial infarction. All clinical specimens in this experiment were obtained upon the agreement of the Ethics Committee of Gansu Provincial Hospital and family members. The clinical research protocol was approved by the Ethics Committee of Gansu Provincial Hospital. The specific clinical data of the patients were collected at the time of admission, including age, gender, weight, physical condition, and hypertension classification , and theSerum biochemical indexes of hepatic and renal function will be affected by many diseases, and hypertensive cerebrovascular disease is no exception. Five mL of venous blood was drawn from the arm and placed in an EP tube containing an anticoagulant, followed by centrifugation at 2000 g for 15 min at room temperature. The supernatant was collected to detect the hepatic and renal function indexes BUN, SCR, AST, and ALT, so as to provide an important theoretical reference for early treatment.The left ventricles of patients were auscultated using a stethoscope in a quiet state, and the heartbeats per minute were recorded 3 times. After the cuff of the sphygmomanometer was wrapped around the patient's arm, the rubber ball was squeezed to gradually elevate the mercury column until no pulse of the brachial artery was heard by the stethoscope, at which moment the value in the sphygmomanometer was the systolic blood pressure. Then, the cuff was slowly deflated, and the value in the sphygmomanometer was the diastolic blood pressure at the moment when the sound turned from strong to weak. In the experimental group, the patients were grouped based on the expressions of serum ADPN, hs-CRP, and sICAM-1, and the cerebrovascular complications were recorded, mainly including cerebral hemorrhage, stroke, and cerebral infarction. The specific diagnostic criteria are as follows: a history of hypertension, heart disease, etc.; acute onset of all or local brain damage; and corresponding lesions or related diseases detected by CT. In the experimental group, ADPN < 2 mg/L, hs − CRP < 4 mg/L, and sICAM − 1 < 500 ng/mL indicated the low expression, otherwise the high expression –19.In patients with hypertension, the biochemical indexes of blood lipids will be changed, so their changes can be detected to indicate the occurrence and development of disease. Five mL of fasting peripheral venous blood was drawn in the morning and placed in the EP tube containing anticoagulant EDTA, followed by centrifugation at 3500 g for 10 min at room temperature. The supernatant was collected to detect the blood lipid indexes TG, TC, LDL, and HDL, so as to provide an important theoretical reference for early treatment.In the morning, 5 mL of peripheral venous blood was drawn on an empty stomach in each group, placed in an EP tube containing anticoagulant EDTA, and centrifuged at 3000 g for 10 min at room temperature. The supernatant was collected to detect the changes in content of serum ADPN, hs-CRP, and sICAM-1 according to the instructions of the ELISA kits (Nanjing Jiancheng Bioengineering Institute). Then, the absorbance of indexes in each group was measured using a microplate reader. The correlation of ADPN, hs-CRP, and sICAM-1 with the incidence rate of cerebrovascular complications was analyzed using the Pearson method.The systolic blood flow velocity (Vs), diastolic blood flow velocity (Vd), mean blood flow velocity (Vm), and pulsatility index (PI) of each blood vessel were observed and recorded using the MEDENG CBA CV-300 cerebrovascular hemodynamic analyzer (probe frequency: 2 MHz) according to the manufacturer's instructions.In each group, 5 mL of fasting peripheral venous blood was drawn in the morning and placed in the EP tube containing anticoagulant EDTA, followed by centrifugation at 3000 g for 10 min at room temperature. The supernatant was collected according to the instructions of the ELISA kit (Nanjing Jiancheng Bioengineering Institute), and changes of serum S100, NSE, and BNDF were detected. Then, the absorbance of indexes in each group was measured using the microplate reader.p < 0.05 suggested that the difference was statistically significant. The bar graph was plotted using GraphPad Prism 5.0.All raw data obtained in the experiments were statistically analyzed using SPSS 21.0 software, and multiple comparisons were performed. The experimental results were expressed as mean ± standard deviation (p < 0.05), indicating the changes in liver and kidney metabolic functions in patients with hypertensive cerebrovascular disease, which can provide a basis for early prediction of disease.As shown in p < 0.05), suggesting the significant changes in blood pressure and heart rate of patients with hypertensive cerebrovascular disease.As shown in p < 0.05), while the content of HDL obviously declined compared with those in the control group (p < 0.05)  , suggestp < 0.05), while that of hs-CRP and sICAM-1 was evidently increased , while the BNDF level was significantly decreased (p < 0.05)  .In the experimental group, the patients were grouped based on the expressions of serum ADPN, hs-CRP, and sICAM-1, and the cerebrovascular complications were recorded. As shown in p < 0.05) and evidently higher PI (p < 0.05)  .p < 0.05), while hs-CRP and sICAM-1 were positively correlated with the incidence rate of cerebrovascular complications (p < 0.05)  .Hypertension is the most important risk factor for cerebral hemorrhage and cerebral infarction, as well as a major risk factor for cerebral hemorrhage. More than 75% of patients with hypertension and more than 80% of patients with cerebral hemorrhage are aged 50-70 years old. Cerebrovascular changes in hypertension, mainly including the increase in the arterial wall thickness, accompanied by the increased media/lumen ratio , are cloADPN synthesized in adipose tissues possesses the antiatherosclerosis, anti-inflammatory, and insulin-sensitizing effects . LindstrIn conclusion, a series of experiments in this study confirm that there are changes in the hepatic and renal function, blood lipids, and hemodynamics in patients with hypertensive cerebrovascular complications, further promoting the development of disease. Such effects can be further verified through animal experiments in the future. This study provides a theoretical basis for the pathogenesis, prevention, and treatment of hypertensive cerebrovascular complications, as well as new ideas for further research.


Bone JN, Magee LA, Singer J, et al. Blood pressure thresholds in pregnancy for identifying maternal and infant risk: a secondary analysis of Community-Level Interventions for Pre-eclampsia (CLIP) trial data. Lancet Glob Health 2021; 9: e1119–28—In table 3 of this Article, in the comparison of blood pressure category and all higher categories, with all lower blood pressure categories, the risk ratios with severe stage 2 hypertension for all adverse outcomes were incorrect and have been updated. These corrections have been made as of Sept 15, 2021.


The Cushing reflex does not appear to have been described in preterm neonates. This case report shows the presence of an active Cushing reflex in a 32-week preterm neonate with hyaline membrane disease.The 1.94 kg Caucasian infant was delivered by caesarean section following concerns about possible maternal infection and fetal compromise. Chest X-ray showed mild-to-moderate hyaline membrane disease and treatment was initiated with supplemental oxygen and nasal continuous positive airway pressure. It is probable that a pneumothorax occurred at 5–6 hours of age, with progression during the day. Interstitial air, pneumomediastinum, and tension pneumothorax were diagnosed on subsequent X-ray, and ultrasound of the brain showed a grade IV intraventricular hemorrhage. A review of the nurses’ recordings of heart rate, blood pressure, and respiratory rate showed a progressive increase in blood pressure accompanied by slowing of the heart rate and irregular respiration. These are features of the Cushing reflex that is elicited in response to raised intracranial pressure.While well-described in older children and adults, in neonates the Cushing reflex has mainly been described in animal experiments and infants who have developed hydrocephalus. It is likely that in this case, the reflex was elicited as a result of a progressive increase in intracranial pressure due to the combination of elevated intrathoracic pressure, obstructed venous return from the brain, and concurrent intraventricular hemorrhage. The case presented shows the clinical course of a 32-week neonate with hyaline membrane disease (HMD) admitted in 2008 to a Level 2 Neonatal Intensive Care Unit (NICU) in a mid-sized South African city. In the absence of specialist neonatologists in that city, care was provided by a generalist pediatrician. In 2018, after 10 years of discussion between various parties, the case found its way into the courts and the authors of this article were engaged to provide expert opinion. From a clinical perspective, the uniqueness of this report is the evidence of an active Cushing reflex in a preterm neonate.The mother was admitted in preterm labor. Corticosteroids were immediately administered but a cesarean section was performed 10 hours later following concerns about a non-reassuring cardiotocographic tracing. The female infant, weighing 1.94 kg, was delivered with Apgar scores of 9 and 10 at 1 and 5 minutes, respectively. The attending pediatrician ordered immediate admission to the NICU, a unit staffed by nurses operating under the direction of pediatricians in private practice, not based in the hospital but available at any time if and when required.2O, and inspired oxygen (FiO2) set at 0.6. Oximetry showed saturation (SpO2) of 95%. Venous blood gas was recorded as pH 7.24; pCO2 56 mmHg; pO2 72 mmHg; bicarbonate 21.9 meq/l. Chest X-ray was reported as showing mild-to-moderate HMD. Based on experience with previous infants of similar weight and gestational age, the attending pediatrician elected to continue with NCPAP, maintaining SpO2 between 87% and 95% with FiO2 ≤ 0.45. Routine admission blood tests including blood cultures were non-contributory. Routine observations included general assessment of neurological function and palpation of the anterior fontanelle. As shown in Fig. 2, SpO2) did not raise specific concerns. Occasional mild desaturations and brief periods of increasing oxygen requirements were noted, all of which responded to adjustments in FiO2. However increasing oxygen requirements from around 11:30 were reported to the attending doctor, who at 13:00 prescribed caffeine.On admission, the infant was noted to be grunting with a respiratory rate of 72 breaths per minute. Nasal continuous positive airway pressure (NCPAP) was applied at 5 cm H2 and the ability to again reduce FiO2. Nursing staff attributed the subsequent increases in respiratory rate to >100 breaths per minute to the caffeine. The pediatrician examined the infant again at around 15:00 and was satisfied with the condition. At no time were nurses alerted by monitoring device alarms to significant bradycardia, apnea, or hypotension, and based on the parameters shown in the figure, were not duly concerned about clinical deterioration until shortly before 02:50 when the infant collapsed. Resuscitation was initiated by the nursing staff, emergency department doctors were immediately summoned to assist, and the attending pediatrician was called to come in urgently. Resuscitation included intubation, initiation of mechanical ventilation, and administration of sodium bicarbonate, calcium, adrenaline, and midazolam. Chest X-ray at the time of collapse showed a left tension pneumothorax, pneumomediastinum, and significant pulmonary interstitial emphysema. An intercostal drain was inserted on the left. Subsequent ultrasound of the brain showed a grade IV intraventricular hemorrhage (IVH) [Shortly after the administration of caffeine there was a drop in respiratory rate, followed by improvements in SpOPhase 1: 06:30–13:00; post-admission stabilization but increasing oxygen requirements from 11:30Phase 2: 13:00–16:00; a clinical event pre- or post-caffeine administration (most likely pneumothorax)Phase 3: 16:00–20:00; post-event stabilizationPhase 4: 20:00–00:30; disturbances typical of Cushing reflexPhase 5: Decompensation and collapse.Sick preterm neonates with significant and progressive disease typically present with evidence of falling blood pressure and episodes of bradycardia and apnea during deterioration. In this infant, regular observations of cardiorespiratory and general neurological status from the time of admission, as well as the infant’s responses to their interventions, therefore appeared to the nursing staff to be satisfactory prior to the collapse shortly before 03:00. However, when cardiovascular parameters of heart rate and blood pressure were superimposed on the respiratory traces, a very different picture emerged. Five discrete phases appeared to be identifiable Fig. :Phase 1:At the onset of Phase 2, three aberrations occurred that are clearly visible on the composite graph: heart rate, respiratory rate, and blood pressure all decreased. These changes have been described and are consistent with the onset of pneumothorax [As shown in Fig. 2 requirement exceeded 0.3 [2 limit of 0.45. This approach is supported by a Danish retrospective review of neonates born between 2000 and 2013 after 32–34 weeks gestation, treated with early NCPAP and FiO2 threshold of 0.4–0.5 [The outcome in this case would most likely have been different if surfactant had been administered. While not strictly in accordance with prevailing international guidelines recommending that surfactant should be administered to smaller preterm infants with HMD if FiOeded 0.3 , faced w 0.4–0.5 . In the 2O [2 rising to 0.45 after 5–6 hours, NCPAP was failing and treatment with surfactant should have been administered at that time. Also worth pointing out is that the elevated respiratory rates shown in Fig. Some discussion around the administration of caffeine and its possible role in pneumothorax is warranted. Caffeine is considered to be a safe drug and pneumothorax is not specifically recognized as a complication of its administration. However, caffeine is known to increase minute ventilation through increases in tidal volume and respiratory muscle activity . In the 2O . It is t2, which, at around 22:30, reached the highest level of the day, while the FiO2 was actually being dialed down (Fig. In patients older than the neonate under discussion, the Cushing’s triad of an increase in systolic blood pressure, slowing of the heart rate, and respiratory irregularity is recognized as an indication of raised ICP. Generally attributed to the body’s response to acutely elevated ICP within a rigid cranial vault and a sign of impending herniation, data are limited for neonates. The open sutures of the neonatal skull no doubt allow some accommodation if/when there is raised ICP, but there are likely limits to the accommodation and it is reasonable to assume that cerebral blood flow may be compromised if there is a significant acute to sub-acute increase in ICP. There is evidence that the reflex exists in neonatal rabbits, manifesting as hypertension, bradycardia, and decreased respiration in response to progressive increases in ICP . The refIt is certainly possible that the Cushing reflex only manifested in this case because the opportunity was missed to treat the infant at ± 6 hours of age, thereby allowing a pathological situation to progress to the point of critically raised ICP. Nonetheless, it is important to note that there may be subtle manifestations of the reflex in a critically ill preterm infant such as this, even in the presence of a compliant cranium with open fontanelles and sutures.


Baroreflex activation therapy (BAT) has been shown to lower blood pressure in patients with resistant hypertension. The purpose of this study was to analyze whether this translates into a reduction of more relevant clinical endpoints.Patients with resistant hypertension were treated with the second-generation BAT system. Records on hospitalization  were obtained from medical insurance companies.p = 0.03). Hospitalizations related to hypertension were significantly decreased from 1.5 ± 1.6/year before BAT to 0.5 ± 0.9/year after BAT (p < 0.01). The cumulative duration of hypertension-related hospital stays was significantly reduced from 8.0 ± 8.7 days/year before BAT to 1.8 ± 4.8 days/year after BAT (p < 0.01). Office cuff blood pressure was 183 ± 27 mmHg over 102 ± 17 mmHg under 6.6 ± 2.0 antihypertensive drugs before BAT and 157 ± 32 mmHg over 91 ± 20 mmHg (both p < 0.01) under 5.9 ± 1.9 antihypertensive drugs (p = 0.09 for number of drugs) at latest follow-up. Daytime ambulatory blood pressure was 164 ± 21 mmHg over 91 ± 14 mmHg before BAT and 153 ± 21 mmHg (p = 0.03) over 89 ± 15 mmHg (p = 0.56) at latest follow-up. Heart rate was 75 ± 16 bpm before BAT and 72 ± 12 bpm at latest follow-up (p = 0.35).Records on hospitalization were available for a period of 1 year before BAT in two patients and 2 years in 22 patients. The total number of hospitalizations per patient was 3.3 ± 3.5/year before BAT and 2.2 ± 2.7/year after BAT  contains supplementary material, which is available to authorized users. Resistant hypertension is a major determinant of cardiovascular complications –4. TheraThe currently available second-generation device has been tested in smaller trials without a control group. The first trial found a 26-mmHg reduction of systolic blood pressure in 30 patients. An indirect comparison of first- and second-generation devices confirmed a similar blood pressure lowering effect –12. In aReduction of blood pressure prevented cardiovascular endpoints in randomized trials with single- or dual-drug therapy . There hTo assess the effect of BAT not only on blood pressure but on a more clinically relevant endpoint, we analyzed the number and duration of hospitalizations in patients with resistant hypertension before and after treatment with BAT.This study is a retrospective analysis of hospitalization data obtained from medical insurance companies and blood pressure recordings performed during routine clinical follow-up of BAT patients.BAT was applied by the second-generation system  as described before , 20. TheThirty consecutive patients with resistant hypertension, i.e. blood pressure ≥ 140/90 mmHg despite antihypertensive therapy with ≥ 3 drugs from different classes including one diuretic and after exclusion of secondary causes of hypertension, treated with BAT at the University of Cologne, Germany, between February 2011 and June 2015 were included in this analysis. BAT is approved in Europe for treatment of resistant hypertension.The primary endpoint of the study was overall and hypertension-related hospitalizations before and after BAT. Secondary endpoints included blood pressure obtained by office cuff measurements and ABPM. Based on our clinical experience with BAT and previous trials, we hypothesized that BAT was associated with a significant reduction in hypertension-related hospitalizations and a significant reduction in blood pressure in our cohort. Data were analyzed retrospectively. The analysis was considered as exploratory, and no effect size was defined as clinically relevant before data analysis was performed.Medical insurance companies of the patients were asked to provide the date and duration of hospitalizations and main diagnosis according to ICD-10 classification. Hospital visits were only counted as a hospitalization if the patient spent at least one night in the hospital; i.e. visits to the out-patient or emergency department with discharge on the same day were not assessed. Data on hospitalizations during 2 years before device implantation were collected as baseline (“before BAT”); hospitalization rates earlier than 2 years before implantation were considered not representative as baseline due to estimated disease progression. Follow-up after device implantation (“after BAT”) varied according to the implantation date of patients; collection of follow-up data ended on July 15, 2016. Number and duration of hospitalizations were annualized to account for different durations of follow-up; only data of fully completed years were included in the analysis. Scheduled hospitalization for implantation of the BAT device was not counted as a hospitalization, while hospitalizations after device implantation but before activation were counted as “after BAT,” to assess all adverse events related to the procedure. Hospitalizations were classified as hypertension-related if ICD-10 codes I.10–I.13 were documented as the main diagnosis (I.15 [secondary hypertension] was excluded). Hospitalizations related to cardiovascular diseases included ICD-10 codes I.00–I.99 (excluding I.10–I.13).Blood pressure measurements were part of the routine follow-up on BAT at the University of Cologne. Patients had monthly follow-up visits until 6 months and were examined in 3- or 6-month intervals thereafter. Office cuff blood pressure measurements were performed by trained physicians or nurses on patients sitting quietly with an appropriately sized cuff placed on the same arm each time, using an automated BPtru device  set to calculate the mean of five measurements taken in 2-min intervals. ABPM was performed by our center or the general physician or cardiologist of the patient using devices of different manufacturers. Since blood pressure values were collected retrospectively and did not follow a predefined schedule, we did not perform blood pressure analyses at specific time-points after BAT activation, but focussed the analysis on the latest follow-up available for each patient.U tests for continuous variables and Fisher’s exact tests for categorial variables (independent samples). The correlation between baseline systolic blood pressure and the reduction of hospitalizations was evaluated by the Spearman rank correlation coefficient. All reported p values are two-sided, and p values < 0.05 were considered statistically significant. As the analyses were regarded as explorative, we did not adjust for multiple testing.Statistical analyses were performed using IBM SPSS Statistics Version 24 . Variables of interest were described using mean values ± standard deviation (SD) or frequencies and percentages. Since sample size was small and we were not confident to have normally distributed data, we used nonparametric tests. To compare baseline and follow-up values, we used Wilcoxon sign rank tests for continuous variables and McNemar tests for categorial variables (paired samples). To compare subgroups of interest, we used Mann–Whitney Graphs were created using SigmaPlot 8.0  and Powerpoint 2016 .Data from 30 patients were included in the analysis. Baseline characteristics of the patients are presented in Table p < 0.01). Blood pressure after implantation but before device activation was available for 10 patients and amounted to 176 ± 34 mmHg over 103 ± 22 mmHg .Office cuff recordings at baseline and latest follow-up were available for 27 patients. The latest follow-up was 652 ± 352 days after activation. Before BAT, office cuff blood pressure was 183 ± 27 mmHg over 102 ± 17 mmHg (Table p = 0.06) over 87 ± 15 mmHg (p = 0.70) at latest follow-up . The percentage of hypertensive systolic blood pressure values during the 24-h monitoring period  decreased significantly from 83 ± 18% before BAT to 70 ± 22% after BAT (p = 0.03). The percentage of patients with mean systolic blood pressure > 180 mmHg was numerically reduced from 23% before BAT to 9% after BAT.The maximum blood pressure during ABPM did not change after BAT (p = 0.35).Heart rate was 75 ± 16 bpm before BAT and 72 ± 12 bpm at latest follow-up . Hospitalization rates related to cardiovascular diseases (except hypertension) or end-organ damage were not altered significantly . Follow-up after BAT activation was 1259 ± 498 days. The number of all-cause hospitalizations was 3.3 ± 3.5/year before BAT and was significantly reduced to 2.2 ± 2.7/year after BAT . First replacement was performed 2.4 ± 0.9 years after initial activation. Duration of hospitalization for replacement was 2.0 ± 1.3 days, when all cases are included in the analysis, and 1.6 ± 0.53 days when excluding one case involving perioperative stroke requiring a prolonged hospitalization period of 14 days.r = −0.453 for number of hospitalizations and r = −0.453 for duration). Subgroup analyses of patients with/without prior renal denervation , age above/below median  and male/female gender  revealed no significant differences between subgroups in the reduction of number or duration of hypertension-related hospitalizations after BAT.Patients with a baseline systolic blood pressure above median (≥ 165 mmHg) showed a trend towards a higher rate and duration of hypertension-related hospitalizations before BAT . After BAT, the reduction of number as well as duration of hypertension-related hospitalizations was numerically higher in patients with baseline systolic blood pressure ≥ 165 mmHg, but these findings were not statistically significant. There was a small correlation between magnitude of baseline systolic blood pressure and the reduction of number and duration of hypertension-related hospitalizations; i.e. the higher systolic blood pressure was at baseline, the more pronounced was the reduction of hospitalizations (p = 0.09). The number of different drug classes was 5.8 ± 1.4 at baseline and 5.6 ± 1.6 at latest follow-up (p = 0.54). The percentage of patients taking a specific class of drugs did not change from baseline to the latest follow-up .At baseline, the number of antihypertensive drugs was 6.6 ± 2.0. It was numerically reduced to 5.9 ± 1.9 drugs at latest follow-up . For medical treatment of hypertension, a beneficial effect on hospitalization rates has been demonstrated [To the best of our knowledge, other device-based therapies for resistant hypertension have not proven a beneficial effect on hospitalization. In the SYMPLICITY II trial , three pnstrated , 25).The rate of all-cause hospitalizations was reduced following BAT, but this difference was solely driven by a significant reduction of hypertension-related hospitalizations, while hospitalizations not related to hypertension were unaffected. This points to a potential causal link between BAT, the observed reduction in blood pressure and the positive effect on hospitalization. Interestingly, not only hospitalization rate was improved, but the duration of hospitalization was reduced in a relevant magnitude. This finding implies that in addition to the reduction in frequency of hypertensive crises requiring inpatient treatment, the severity and refractoriness to treatment may have improved after BAT.Consistent with a significant reduction of office cuff blood pressure, daytime systolic blood pressure assessed by ABPM was significantly reduced after BAT. Nighttime and overall ABPM were numerically reduced, but this did not reach statistical significance. This lack of statistical significance is probably related to the high standard deviation and low number of patients, since significant reductions in nighttime and overall ABPM were described in other trials and were of similar magnitude as in our study , 14. HowBefore data analysis was performed, no effect size was defined as clinically relevant. Few studies focussed on the effect of antihypertensive treatment on hospitalization, and definitions of hospitalization, underlying causes and statistical methods varied across studies; thus, interpretation and comparison of effect sizes is difficult. For instance, poor adherence to medication was associated with a hazard ratio of 1.47 for all-cause hospitalization as compared to good adherence . LosartaThis study is subject to the limitations inherent in retrospective analyses and small patient numbers. However, our findings regarding blood pressure reduction are consistent with a number of previous trials, and it is well-known and plausible that such a significant reduction in blood pressure has a beneficial effect on hospitalization.In addition, a placebo or Hawthorne effect is likely to have contributed to the observed blood pressure reduction and subsequent decrease in hospitalizations, especially in view of the invasive nature of BAT. The importance of such effects in interventional treatment of hypertension is underlined by the overestimation of therapeutic benefit in non-sham-controlled as compared to sham-controlled trials , 29. HowData on hospitalizations were provided from medical insurance companies, which collect dates and ICD-10-coded main diagnoses of hospitalizations from hospitals for reimbursement purposes. Therefore, coding errors, especially regarding the main diagnosis leading to hospitalization, cannot be excluded. It was not possible to verify duration and cause of hospital stays, since we did not have access to source data. Due to the high number of hospitalizations and the identical mode of data acquisition before and after BAT, this is unlikely to have influenced the overall results of the study.Although we used an automated device for office cuff blood pressure assessments and routinely performed recordings in patients sitting quietly, there was no standardized protocol for office cuff measurements. ABPM measurements were even performed by different healthcare providers with devices from different manufacturers and did not follow a specified protocol. This may have contributed to the high standard deviation of blood pressure values and limits interpretation of data.We provide first evidence that the rate and duration of hospitalizations in patients with severe resistant hypertension may be reduced by BAT. This finding suggests that the known positive effect of BAT on blood pressure may potentially translate into a reduction of relevant clinical endpoints. Future studies involving larger patient numbers and addressing the effect of BAT on cardiovascular and cerebrovascular endpoints including mortality are needed and encouraged by the present findings. Moreover, the potential effect of BAT on hospitalizations may contribute to the cost-effectiveness of this therapy, which deserves further attention in future trials.Supplementary file1 (DOCX 60 kb)Supplementary file2 (DOCX 92 kb)Below is the link to the electronic supplementary material.


Background: Cardiovascular events (CVEs) are the first cause of death in patients with psoriatic arthritis (PsA). Depression is a recognized risk factor in cardiovascular events and is frequently associated with PsA. Flow-mediated dilatation (FMD) is a widely used method for assessing endothelial dysfunction, a parameter with strong prognostic implications for CVEs. The study aims to explore the relationship between FMD, depressive symptoms and serum cytokines in a cohort of patients with PsA.Patients and Methods: FMD was assessed in 50 consecutive PsA patients aged between 30 and 75 years without known cerebrovascular and coronary heart disease or diabetes. Depressive symptoms were reported using the related subscale of the Hospital Anxiety and Depression Scale (HDS). Disease features, activity indexes, and adjusted Framingham risk score (aFRS) were calculated. Serum level of IL-6, TNF-α, and IL-17A were also assessed.Results: In PsA patients  score 14.0 ± 9.4) FMD inversely correlated with the severity of depressive symptoms according to HDS , age , aFRS , duration of PsA , intensity of pain , and DAPSA . No statistically significant correlation was found between FMD or HDS and serum cytokines concentrations. HDS predicted FMD in a model adjusted for age, aFRS, PsA duration, and pain intensity , with depressive symptoms contributing directly to 6.4% of the variance.Conclusions: Depressive symptoms correlate with endothelial dysfunction with an exposure-response pattern in our cohort of PsA patients. Cardiovascular events (CVEs) are the leading cause of death in patients affected by psoriatic arthritis (PsA), who indeed present an increased rate of myocardial infarction and stroke . NonetheEndothelial dysfunction (ED) is the inability of an artery to dilate in response to chemical or physical stimuli due to a reduced nitric oxide (NO) availability. ED plays a key role in early atherosclerosis and has the power to predict CVEs such as stroke, myocardial infarction, and cardiovascular death  consisteReduced FMD has been reported in both PsA patients  and deprThe aim of this study is therefore to evaluate the relationship of ED evaluated by FMD with depressive symptoms and serum cytokines in a cohort of PsA patients.The study has a comparative cross-sectional design. The protocol has been approved by the Ethics Committee of Fondazione Policlinico Universitario A. Gemelli-IRCCS (FPG), Rome (Protocol n.0014580/18), and written informed consent was obtained from all participants. Consecutive patients, aged between 30 and 75 years who met classification criteria for psoriatic arthritis (CASPAR)  and on sDuration of PsA, history of peripheral arthritis, axial disease, dactylitis, enthesitis, skin disease and nail disease, pain intensity and patient global assessment (PtGA) on a 10-cm visual analog scale, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) values were registered. Systemic, cutaneous, and articular examination—including tender and swollen joint count—was performed for all patients. Disease Activity in Psoriatic Arthritis (DAPSA) index and Psoriasis Area Severity Index (PASI) were calculated to assess disease activity. The use of conventional and biologic disease-modifying antirheumatic drugs (DMARDs) was noted.2) and abdominal obesity  were reported. Baseline resting blood pressure was measured by auscultatory technique, recording the average of three consecutive measures. Total cholesterol, high- (HDL) and low-density (LDL) lipoprotein cholesterol, and triglycerides were assessed before the visit according to standard practice, and atherogenic index of plasma (AIP) and LDL/HDL cholesterol ratio were computed. High-risk lipid profile has been defined as AIP >0.5 or LDL/HDL cholesterol ratio >3.5 in men and >3.0 in women  and sedentary lifestyle were recorded. Body mass index (BMI) and waist-to-hip ratio (WHR) were recorded as well as proportion of patients with obesity (BMI ≥30 kg/min women . Ongoingin women .Framingham risk score (FRS)  was usedThe presence of depression and the severity of psychological symptoms were evaluated by an experienced psychologist blinded to the other clinical data using the depression subscale of the Hospital Anxiety and Depression Scale (HDS). This scale was chosen because the items do not include somatic symptoms that may be caused by immunosuppressive drugs and extra-articular physical manifestations of PsA. Although it is not a basis for the clinical diagnosis of depression, a validated cutoff of 8 was used to define patients with significative depressive symptoms, who were referred to as depressed in this paper .FMD was evaluated within 2 days from the screening visit by an experienced angiologist blinded to other clinical data. All participants were studied in the morning beginning between 8:00 and 9:00 am, fasting, and having avoided alcohol for at least 24 h and caffeine for at least 12 h. Vasoactive and non-steroidal anti-inflammatory medications were withheld for 48 h before the test. Subjects rested supine in a quiet, temperature-controlled environment for 20 min before the exam. The right brachial artery was imaged in the longitudinal plane 2 to 15 cm proximal to the antecubital fossa using a 17–5 MHz linear array transducer connected to an iU22 ultrasound machine . Depth and gain were selected to enable optimal identification of the anterior and posterior intimal interface between lumen and vessel wall on 2D grayscale images. Baseline images were then acquired. Blood flow was measured from the pulsed wave Doppler signal with a 60° insonation angle. After recording baseline values, a sphygmomanometer cuff was applied around the forearm, inflated to 250 mmHg, and left in place for 5 min, causing forearm ischemia and consequent dilation of downstream resistance vessels. Blood flow was measured over the first 15 s after cuff deflation, whereas arterial images were acquired between 60 and 90 s after cuff release  with a sensitivity of the test of 0.7 pg/ml. Serum levels of TNF-α and IL-17A were simultaneously measured by Luminex assay  on a Luminex xMAP system . Results were analyzed using a dedicated Bio-Plex Manager software and are expressed in picograms per milliliter.rs) as indicated. The relationship between FMD and natural dichotomous variables was tested by point-biserial correlation (ρ) after ruling out the presence of significant outliers by boxplot and checking the homogeneity of variances by Levene's test. Hierarchical multivariate linear analyses were done with the percentage of FMD as the dependent variable. Variables showing a correlation with FMD were included in the model as predictors. The first block included predictors of FMD shared with general population , in the second block the model was adjusted for potential PsA-related predictors, in the last block HDS was added to the model. HDS was added in the last step in order to estimate the percentage of the total variance of FMD explained by depressive symptoms after controlling for potential confounding variables. Statistical significance of F modification was reported for each step. Independence of residuals was assessed by Durbin-Watson test, multicollinearity was excluded for ρ <0.700 for each couple of predictors. Homoscedasticity and normality of residual distribution were checked by visual inspection of a plot of standardized residuals vs. standardized predicted values and a probability plot, respectively. All tests were two sided. Statistical significance was defined as p < 0.05.Data were analyzed using IBM SPSS Statistics v26.0 . Categorical variables were reported as numbers and percentages. Continuous variables were reported as mean ± SD or median and interquartile range (IQR), according to the distribution of the data. Normality of continuous variables was assessed by inspection of Q–Q (quantile-quantile) plots. Variables without Gaussian distribution were normalized using the logarithm transformation, when effective. Linearity of the relationship between continuous variables and the presence of significant outliers were assessed by scatterplot. The relationship between FMD and HDS or other paired continuous variables was explored using Pearson's (ρ) or Spearman's coefficient  of 33% in PsA patients defined by HDS ≥8, and an expected FMD value of 6.5 ± 3.0 in patients with depressed symptoms and 8.5 ± 3.0 in the other PsA patients. The α was set as double-sided 0.05 (5% level of significance), and β was set as 0.2 (90% power). Thus, we set the sample size as Fifty consecutive PsA patients were enrolled; the clinical characteristics of the study cohort are summarized in Four patients (8.0%) were in high disease activity, 19 (38.0%) in moderate disease activity, 20 (40.0%) in low disease activity and 7 (14.0%) in remission according to DAPSA score while under treatment. Twenty (40.0%) patients were depressed according to HDS ≥8 with an average HDS of 6.8 ±3 0.3. Depressed and non-depressed patients did not significantly differ according to disease features and serum levels of IL-6, TNF-α, and IL-17A .p = 0.01) while they did not differ according to the other recorded cardiovascular risk factors . Depressed patients were less frequently male , explaining 11% of the variation in endothelium-dependent vasodilation. The relationship was similar if the cutoff of HDS ≥8 was considered to define depressed patients . Regarding traditional risk factors for CVD, there was a statistically significant, strong negative correlation between FMD and age  and a moderate negative correlation with aFRS  and Log(aFRS) . Of notice, aFRS was normalized by log transformation because of the markedly skewed distribution of the data.Single correlations of FMD and HDS with traditional risk factors for CVD and other clinical features are shown in p = 0.024), with females showing higher depressive scores compared with males (7.7 ± 2.8 vs. 5.5 ± 3.6). As concerns disease characteristics, FMD correlated with PsA disease duration , intensity of pain , and DAPSA  while HDS correlated with TJC on 68 joints , the intensity of pain  and DAPSA   , 2. Notap < 0.001 and ρ = 0.791, p < 0.001, respectively) and each other , these measures have not been entered simultaneously in the model, to avoid multicollinearity. We decided to use pain intensity in the model since it was included in DAPSA formula and because psychological factors have an established role in the experience of pain. Therefore, hierarchical regression was run to predict FMD, entering as variables age, baseline arterial diameter, and Log(aFRS) in the first step. PsA duration and pain intensity were added in the second step and HDS in the third step. Regression coefficient (R2)values are reported in F = 6.88, p < 0.001) with age independently associated with the endothelial function . PsA-related variables in the second step, the explained variance increased up to 40.8%  and pain intensity  and age  were both significantly associated with the endothelial function in the adjusted model. The inclusion of HDS in the third step contributed to an additional 6.4% of the variance in predicting FMD . It should be noted that at the last step the correlation between FMD and HDS remained significant on multivariate regression analysis  suggesting an independent effect of the depressed mood on endothelial function. Age was also significantly associated with FMD  in the full-enter model.Multiple regression analyses was carried out to assess the relative contribution of the variables in predicting FMD. Predictors were chosen according to both theoretical importance and statistical significance on bivariate correlation. Since pain intensity and PtGA were both highly correlated with DAPSA , disease duration, and pain severity. In the multivariable linear model, the largest variation of FMD was explained by age and aFRS, as reported in the general non-psoriatic population , 24, whiThese data allow us to speculate that the gap between predicted and actual incidence of CVEs could be in part explained by a quote of endothelial dysfunction related to an eventual concurrent depressive status. In this perspective, the investigation of depressive symptoms in PsA could contribute to a more accurate stratification of cardiovascular risk, since mood disorders are often under-recognized and under-treated in these patients . It shouMechanisms of ED in PsA or depression are still unclear, but they are expected to be multiple and overlapping. The crosstalk between central and peripheral nervous system, the inflammatory and autoimmune response, and the cardiovascular system is complex , and ourThe limitations of the present study include the lack of a control group and the cross-sectional design with the consequent inadequacy to more strongly support the relationship between endothelial dysfunction and depressive symptoms. Moreover, we did not directly measure potential non-inflammatory determinants of ED nor the cumulative exposure to inflammation or depressive mood . Lastly,The study has some strengths, too. To the best of our knowledge, this is the first study assessing the relationship between ED and depressive symptoms in patients with PsA. The patients have been thoroughly studied in terms of traditional cardiovascular risk factors, and we applied stringent exclusion criteria in order to limit confounding factors. Patients treated with antidepressants, for example, were excluded from the study because of the effect of antidepressant drugs on endothelial function .In our cohort of PsA patients, depressive symptoms were related to ED. If validated in longitudinal studies, this evidence would encourage a systematic research of depressive symptoms as a part of a correct assessment of cardiovascular risk in PsA, helping to raise the effectiveness of prevention strategies. The future research agenda should clarify if the choice of both immunosuppressant and antidepressant treatment in PsA could be personalized according to effects on endothelium, as part of cardiovascular prevention strategies.The original contributions presented in the study are included in the article/The protocol and the template informed consent forms were reviewed and approved by Committee on Research Ethics of Catholic University of the Sacred Heart. The patients/participants provided their written informed consent to participate in this study.All authors gave substantial contributions to the conception or design of the work, acquisition, analysis, or interpretation of data, drafting the work or revising it critically for important intellectual content, and final approval of the version published.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.


In previous studies, the difficulty of surgery has rarely been used as a research object. Our study aimed to develop a predictive model to enable preoperative prediction of the technical difficulty of video-assisted thoracoscopic lobectomy and mediastinal lymph node dissection using retrospective data and to validate our findings prospectively.Collected data according to the designed data table and took the operation time as the outcome variable. A nomogram to predict the difficulty of surgery was established through Lasso logistic regression. The prospective datasets were analyzed and the outcome was the operation time.p < 0.001, OR, odds ratio = 0.89, 95% CI, confidence interval = 0.84–0.94), FEV1/pred FEV1 (forced expiratory volume in the first second/forced expiratory volume in the first second in predicted) , history of lung disease , and mediastinal lymph node enlargement or calcification . We used ROC (receiver operating characteristic) curves to evaluate the model. The training set AUC (area under curve) value was 0.877, the test set’s AUC was 0.789, and the model had a good calibration curve. In a prospective study, the data obtained in the research cohort were brought into the model again for verification, and the AUC value was 0.772.This retrospective study enrolled 351 patients and 85 patients were included in the prospective datasets. The variables in the retrospective research were selected by Lasso logistic regression (only used for modeling and not screening), and four significantly related influencing factors were obtained: FEV1/FVC   were related to the difficulty. Lung cancer has a high incidence and mortality . AccordiThe retrospective data included patients who underwent VATS lobectomy and mediastinal lymph node dissection at our center from 2016.1.1 to 2020.3.31, which were all performed by the same surgeon (an experienced chief thoracic surgeon). The size of the main lesion was less than 3 cm, the surgical site was only a single lobe, intraoperative frozen pathology identified lung cancer, and mediastinal lymph node dissection was performed. There were 2 incisions  for all patients. Patients who were diagnosed with lung cancer before an operation or only underwent lobectomy without lymph node dissection were excluded. Those with lesions not limited to a single lobe (clearly defined as lung cancer lesions) were excluded. Those who underwent multilobe or sublobe surgery or underwent neoadjuvant therapy before the operation were also excluded. All the patients received written informed consent prior to the surgery. The study was approved by Ethics Committee of Department of Thoracic Surgery, Tianjin Chest Hospital.λ = 1•se (standard eorror) as the variables used to build the Logistics regression model. The model was evaluated with ROC (Receiver Operating Characteristic) curves, calibration curves, and DCA  curves, and finally a nomogram was constructed [We collected the preoperative information and possible influencing factors of the patients, including the patients’ gender, age, height, weight, liver and kidney function, routine blood tests, coagulation six items, and smoking history. We also collected data relevant to the surgical treatment, including a history of lung diseases , the presence of coronary heart disease , lung function assessments, and whether mediastinal lymph node enlargement or calcification was observed on chest CT. The operation time was selected as the outcome variable and used to represent the difficulty of the operation. R, version 4.0.4 was used to perform all of the data analyses. We used Lasso logistic regression analysis to build the model. We chose the variables that were retained when structed , 6. The Data collection: Patients met the admission criteria (same to the retrospective study’s criteria) for VATS lobectomy and mediastinal lymph node dissection in our center 2021.4.1 to 2021.10.31 were included. We collected preoperative information from all patients following the data collection form designed for the retrospective study. We incorporated the data into the model constructed from the retrospective data.There were 437 patients who met the criteria. After removing some samples with missing data, a total of 351 cases were finally included and 25 variables were evaluated (according to the sample accounts: variable > 10:1). The 25 variables are as follows: age, gender, prior lung disease, coronary heart disease, smoking, lobe, mediastinal lymph node enlargement or calcification, height, weight, FVC/ pred FVC, FEV1/predFEV1, FEV1/FVC, DLCO.SB, white blood cell, absolute neutrophil count, red blood cell, hemoglobin, prothrombin time, activated partial thromboplastin time, thrombin time, D. dimer, albumin, creatinine, fissure, and neutrophilic granulocyte percent. A total of 351 patients were randomly divided into a training set and a test set at a ratio of 3 to 1. Their detailed baseline information is shown in Tables *Evaluation of the prediction nomogram results:After calculating the ROC (receiver operating characteristic) curve, the AUC (area under curve) value in the training set was 0.877 Fig. a. The cuThe final number of patients who underwent VATS lobectomy and mediastinal lymph node dissection was 85. We followed the scheme shown in the flowchart and fitted the prediction results for the prospective data (AUC = 0.772), which confirmed the accuracy of the model established in our retrospective analysis and validated our research Table .Table 3CIn recent years, with the application of low-dose chest CT in the early screening of lung cancer, the detection rate and consultation rate of small lung nodules have gradually increased . VATS lo. [p = 0.023), age (p = 0.000), body mass index (BMI) (p = 0.000) and pre-operative endoscopic retrograde cholangiopancreatography (ERCP) (p = 0.001) are the variables associated with the level of the surgical difficulty of the laparoscopic cholecystectomy. Escal et al. [2 (P = 0.021), coloanal anastomosis  (P = 0.034), intertuberous distance less than 10.1 cm (P = 0.041) and mesorectal fat area exceeding 20.7 cm2 (P = 0.051). Since there is no objective standard to measure the difficulty of the operation, most of the previous studies have used the operation time, blood loss, postoperative complications, etc., to estimate the difficulty of the operation [Previous studies have established predictive models for laparoscopic cholecystectomy , predict.  demonstrl et al.  proposedperation –15. The Our results show that a history of lung disease (lung surgery history), accompanied by mediastinal lymph node enlargement or calcification, FEV1/FVC on the lung function test and FEV1 on the lung function test as a percentage of the predicted value would lead to a prolongation of the operation time to varying degrees. For the four related variables, we applied the variance inflation factor to detect the collinearity. The results are as follows: history of lung disease (vif = 1.01), mediastinal lymphadenopathy or calcification vif = 1.09) FEV1/FVC on the lung function test (vif = 1.61) FEV1 as a percentage of the predicted value on the lung function test (vif = 1.63), when 0 < vif < 10, there is no collinearity among related variables, which indicated that the four related variables were not confounded by each other. Some studies have shown that age, gender and BMI have an impact on the duration of surgery, but the above factors were not significantly correlated in our study  FEV1/FVC. CoagulaDue to the large number of preoperative variables included, we used Lasso screening in this study. In the end, we did not include fissure and lung lobe variables in the final model. As an influencing factor, lung fissure showed a correlation with the length of operation in the univariate logistics regression. However, in the two-way stepwise regression and Lasso regression, the lung fissure was not included in the final meaningful variable. According to the PROBAST score, it is a biased approach to use single-factor regression to screen first, and then multi-factor regression to build a model for the variables selected by single-factor regression. Therefore, we did not adopt this traditional model building method. We believe that for a complete model, it is appropriate to include all variables to be screened into the model from the very beginning . We drewThe following points are unavoidable problems in our research. First, we chose the operation time to reflect the difficulty of the operation. In most cases, it can be considered that the longer the operation time, the greater the difficulty. It is difficult to find a gold standard for objectively judging the difficulty of an operation. Second, some of the factors that complicate surgeries are difficult to predict or know about in advance, such as pleural adhesions, portal lymph nodes that are difficult to completely remove, or bleeding due to intraoperative mishandling. Finally, as mentioned in above, some preoperative prediction variables are difficult to obtain. This study is more committed to some simple variables that are easy to obtain in the routine clinical diagnosis and treatment process. These variables acquired from the general information of patients or the results of non-invasive routine examination, therefore, the accuracy may be slightly insufficient compared with the results of invasive examination.Our retrospective study identified four preoperative variables that are correlated with a longer surgical time and can be presumed to reflect more difficult surgical procedures. Our prospective study verified that the variables in the predictive model  are related to the difficulty of the surgery. Based on these results, we recommend preoperative evaluation of patients undergoing VATS lobectomy and mediastinal lymph node dissection. These findings need to be validated in a sufficiently large prospective multicenter study. This model will become an important auxiliary tool for planning clinical programs.


IntroductionNecrotizing soft tissue infection (NSTI) of the upper extremity (UE) is a rapidly progressing infection that requires early diagnosis and emergent treatment to decrease risks of loss of limb or life. Clinical presentation, particularly of early NSTI, can appear similar to serious cellulitis or abscess. The purpose of this study was to identify factors that are associated with NSTI rather than serious cellulitis and abscess to differentiate patients with similar clinical presentations.MethodsThis study uses a retrospective cohort design that compares patients ultimately diagnosed with UE NSTI versus those diagnosed with UE serious cellulitis or abscess. Cohorts were matched using the Laboratory Risk Indicators for Necrotizing Fasciitis (LRINEC) score in the setting of UE soft tissue infection. Laboratory values, vital signs, subjective symptoms, and social factors including substance abuse and domiciled status were recorded. Continuous variables were compared using the Mann-Whitney U test, whereas categorical variables were compared using the chi-squared test or the Fisher exact test . A binary logistic regression for continuous and categorical variables was also performed. Significance was set at p<0.05. Univariate and multivariate analyses were performed.ResultsMultivariate statistical analysis and clinical interpretation of data identified four factors more associated with a diagnosis of NSTI than serious cellulitis or abscess: elevated lactate on hospital presentation, a patient-reported history of fever, male gender, and homelessness. ConclusionsIn patients with upper extremity infections, the clinical presentation of NSTI and serious cellulitis or abscess may appear similar. In this retrospective cohort of patients matched with LRINEC scores, elevated lactate, subjective fever, male gender, and homelessness were significantly associated with NSTI rather than serious cellulitis or abscess.  Necrotizing soft tissue infection (NSTI) is a rapidly advancing, necrotizing infection of the skin, subcutaneous tissue, and fascia . Upper eThe first step in efficiently treating NSTI is diagnosing the condition . RecogniIn 2004, a diagnostic scoring system called the Laboratory Risk Indicators for Necrotizing Fasciitis (LRINEC) score was created for this purpose . The goaThe goal of this study is to compare a matched retrospective cohort of patients with UE NSTI to those with serious cellulitis and abscess. Even if LRINEC scores cannot be reliably used to diagnose NSTI, they can be used to identify patients with similar laboratory findings on presentation. In our experience, this is often the very group of patients where the diagnosis of NSTI versus serious cellulitis or abscess is clinically challenging. Within these two groups of similar LRINEC scores, this study identifies factors associated with NSTI rather than serious cellulitis or abscess to help in the clinical differentiation between these diagnoses that require different treatments.We hypothesized that certain laboratory findings, some within the LRINEC score, such as the white blood cell count (WBC), and some not accounted for by the LRINEC score, such as the lactate, may be associated with NSTI. We further hypothesized that vital signs at the emergency department presentation may differ between the two groups. Finally, we hypothesized that social conditions - in particular intravenous (IV) substance abuse and housing status - may be associated with NSTI versus serious cellulitis and abscess. All materials and methods in this study have been approved by the Institutional Review Board (IRB), and all necessary HIPAA consent has been received. The research meets all applicable standards with regard to the ethics of experimentation and research integrity. The paper has been submitted with full responsibility, following due ethical procedure, and there is no duplicate publication, fraud, plagiarism, or concern about animal or human experimentation.Forty-two consecutive, surgically confirmed cases of UE NSTI from a single academic institution over a four-year period (2016-2019) were reviewed. Two patients were excluded: one with leukemia and lab abnormalities due to both leukemia and NSTI; and one who transferred to another hospital before NSTI work-up and care was complete. Thus, 40 patients were analyzed in the NSTI study. A control population of 40 consecutive cases of UE serious cellulitis and/or abscess were also reviewed. The control population was matched to the NSTI cohort through average LRINEC scores. Because the average LRINEC score for the NSTI group was expectedly elevated, eligibility for the control group included a LRINEC score of 3 or greater. The goal of this design was to focus on the cases where it is challenging to clinically differentiate between NSTI and cellulitis or abscess. All cases and controls were treated at a major urban, safety-net hospital.For all included patients, variables collected for data analysis were grouped into one of three categories: lab values, vital signs at Emergency Department (ED) presentation, and qualitative data on symptoms and social factors.Lab values collected for each patient included LRINEC score and its six components , erythrocyte sedimentation rate (ESR), lactate, and international normalized ratio (INR). Vital signs at ED presentation that were collected for each patient include maximum temperature (Tmax), maximum heart rate (HRmax), maximum respiratory rate (RRmax), maximum systolic blood pressure (SBPmax), minimum systolic blood pressure (SBPmin), maximum diastolic blood pressure (DBPmax), minimum diastolic blood pressure (DBPmin), maximum mean arterial pressure (MAPmax), minimum mean arterial blood pressure (MAPmin), change in systolic blood pressure (dSBP), change in mean arterial pressure (dMAP), maximum pulse pressure (PPmax), and minimum pulse pressure (PPmin). Additional identifying information, including age and time to presentation, were also grouped into this category. The patient and infection characteristic variables recorded for each case include patient gender, laterality of injury (right or left), homelessness, patient provided history of recent intravenous substance use, subjective fever, and objective fever.For our statistical analyses, all continuous variables were compared with Mann-Whitney U, whereas categorical variables were compared with chi-square test or Fisher exact test . A binary logistic regression for continuous and categorical variables was also performed. Significance was set at p<0.05. Univariate and multivariate analysis was performed.In analysis of the quantitative date: lab results and vital signs, univariate and multivariate analyses were performed. Univariate analysis of lab values identified statistically significant differences in two variables - WBC and lactate Table . WBC val 2 = 15.05, p < 0.001). Additionally, patients in the NSTI cohort were more likely to abuse IV drugs (65.0%) than patients in the cellulitis and abscess cohort (27.5%) . Patients with NSTI diagnosis were more likely to have self-reported a subjective fever (50.0%) than patients with cellulitis or abscess (7.9%) . In univariate analysis, patients with NSTI (70%)  were less likely to be male than cellulitis and abscess patients (92.5%), although the majority of patients in both groups were male. In the multivariate analysis, subjective fever , homelessness , and gender  all remained statistically significant  infection - a cause of both NSTI and cellulitis/abscess -among a homeless population with an incidence of up to 53 times the domiciled population ,26. HoweThough both study populations contained a majority of male patients, gender showed statistical significance in both univariate and multivariate analysis. The group of patients with NSTI was overwhelmingly male compared to the group of patients with serious cellulitis and abscesses. This finding is consistent with prior studies reporting higher rates of both cellulitis ,28 and NAn additional statistically significant variable found in the analysis of our data is a history of subjective fevers. Although subjective fever was more associated with NSTI versus serious cellulitis and abscess, measured temperature and the presence of an objective fever in the emergency department were not significantly associated with one diagnostic group on either univariate or multivariate analysis. Subjective reports of symptoms have been linked to NSTI diagnosis previously, but this is the first association between UE NSTI and subjective fever . There are several weaknesses of this study. Firstly, this is a single-center, retrospective study with a relatively small sample size that may not be generalizable to other patient populations. Our institution is an academic, large, urban, safety-net hospital and may have a baseline patient population different from other institutions. In our patient population, UE NSTI seems to disproportionately affect an under-researched and under-served population of individuals with a high rate of IV drug abuse and homelessness. Additionally, some metrics used in this study (such as subjective fever) were patient-reported and therefore we were not able to verify their accuracy. Finally, because NSTI is a time-sensitive diagnosis, one laboratory value should not delay proper treatment. As such, the results of our study should be interpreted with caution. Future studies to hone our early diagnosis of NSTI versus serious cellulitis and abscess should be prospective and, instead of using LRINEC scores to match a cohort, could identify patients on clinical presentation where the diagnosis of NSTI versus serious cellulitis and abscess is in question. In conclusion, swift and reliable differentiation of UE NSTI from serious abscess and cellulitis is of vital clinical importance. This may lead to a limb or life-saving surgical intervention. It is often clinically challenging to accurately differentiate between these illnesses. In cases where the clinical and laboratory evaluation may not give a clear diagnosis, an elevated WBC, lactate, homelessness, and subjective fever should lead clinicians to an increased consideration of UE NSTI for their diagnosis.


Aims of the study were to evaluate the association between gender and vascular access (arteriovenous fistula (AVF) or central venous catheter (CVC)) used at the start of hemodialysis (HD) and to investigate the association between gender and 1-year mortality. (2) Methods: The study includes 9068 adult chronic HD patients  registered in the Lazio Regional Dialysis Register (January 2008–December 2018). Multivariable logistic regression models were used to investigate the associations between gender and type of vascular access (AVF vs. CVC) and between gender and 1-year mortality. Interactions between gender and socio-demographic and clinical variables were tested adding the interaction terms in the final model. (3) Results: Females were older, had lower educational level and lower rate of self-sufficiency compared to males. Overall, CVC was used in 51.2% of patients. Females were less likely to use AVF for HD initiation than males. 1354 out of 8215 (16.5%) individuals died at the end of the follow-up period. Interaction term between gender and vascular access was significant in the adjusted model. From stratified analyses by vascular access, OR female vs. male (AVF) = 0.65; 95% CI 0.48–0.87 and OR female vs. male (CVC) = 0.88; 95% CI 0.75–1.04 were found. (4) Conclusions: This prospective population-based cohort study in a large Italian Region showed that in females starting chronic HD AVF was less common respect to men. The better 1-year survival of females is more evident among those women with AVF. Reducing gender disparity in access to AVF represents a key point in the management of HD patients. Chronic kidney disease (CKD) is a global health burden and an important risk factor for cardiovascular disease. Indeed, in 2017, CKD affected 697.5 million of individuals worldwide [According to the 2019 Annual Data Report by United States Renal Data System the overall prevalence of CKD stages 1–5) increased from 13.8% in 2016 to 14.5% in 2017 [ increaseImportant gender differences were widely demonstrated in specific medical conditions, in particular in cardiology. These include differences in clinical features, risk factors, disease progression, and access to effective care between men and women ,7. RecenLongevity on HD is directly proportional to the quality of HD which in turn depends on the reliability and integrity of the vascular access . VasculaIn the Lazio Region, the Regional Dialysis and Transplantation Registry (RRDTL), active since 1994 (DGR n. 7940/1987) and established by Regional Law 9/2010, is a tool of great importance for epidemiological monitoring, regional health planning, evaluation of quality of care and promotion of scientific research activities . The larUsing the data of the RRDTL, the aims of the present study are: (1) to evaluate the association between gender and type of vascular access used at the start of hemodialysis (AVF or CVC); (2) to investigate the association between gender and 1-year mortality. The source of the data is the RRDTL which contains information on chronic HD patients treated in all public and private dialysis Centers accredited in Lazio Region . It collects information on socio-demographic and clinical conditions of patients, type of dialysis and pharmacological treatments. Dialysis Centers fill in the data of own chronic HD patients at the start of renal replacement therapy and update them at least once a year. Every change such as recovery of renal function, shift to another dialysis Center, kidney transplantation or death must be communicated. The study includes ESRD patients aged 18 years and over who started chronic HD (incident patients) between January 2008 and December 2018. Exclusion criteria were, previous failed AVF and having AV graft.The primary outcome of the study was the type of vascular access recorded at the start of hemodialysis: AVF or CVC. Gender, categorized as female and male, was considered as predictor. The secondary outcome is the 1-year mortality in incident patents between January 2008 and December 2017 to ensure a one-year follow-up for all patients. Data on mortality was obtained from the Regional Mortality Registry.Gender, categorized as male and female, was considered as the main exposure in this study.Based on the information reported in the RRDTL, the following socio-demographic variables were collected at the start of HD: age at incidence  and educational qualification . Furthermore, we considered both clinical variables such as body mass index  and self-sufficiency  ,33 and cType of dialysis Center (public or private), pre-dialysis counselling .Serum creatinine (mg/dL), Hb (g/dL), CPK (U/L), serum phosphate level (mg/dL), serum albumin (g/L).t-test or Wilcoxon rank sum test for continuous variables.Socio-demographic, clinical and care-related variables are presented as percentage or mean ± std according to gender  and type of vascular access (AVF or CVC) for incident patients. Bivariate relationships between socio-demographic, clinical and care-related variables, on the one hand, and type of vascular access and gender on the other hand, were tested with the chi-square test or Fisher’s exact for categorical variables and by p-value χ2 < 0.05) were introduced in the multivariable model with the stepwise procedure. Comparative risk estimates were expressed as odds ratios (OR) and 95% CI.Univariable and multivariable logistic regression models were used to investigate the associations between gender and type of vascular access (AVF vs. CVC). Variables significantly associated with the outcome in the univariable analysis  were introduced in the multivariable model with the stepwise procedure. Comparative risk estimates were expressed as odds ratios (OR) and 95% CI.Variables significantly associated with the outcome in the univariable analysis .Statistical significance was set at a 2-tailed In the cohort of 9068 incident chronic HD patients the majority was male (64.7%) with a mean age of 68.2 ± 14.3 years. The baseline characteristics of the entire population at the start of HD according to gender are shown in n = 1344) were females. The baseline characteristics of the entire population at the start of HD according to type of vascular access are shown in Patients who started HD using AVF were predominantly male (69.6 vs. 60.1%).They were younger , had higher educational level (37.2 vs. 31.1%), higher rate of complete self-sufficiency (58.0 vs. 36.1%) than patients starting HD with CVC.Moreover, patients starting with AVF had higher rate of obesity (14.5 vs. 13.5%), cardiovascular risk factors (80.5 vs. 75.4%), higher rate of afference to private dialysis Centers (65.8 vs. 59.6) and higher rate of early referral to nephrologist (86.0 vs. 65.2) than patients starting with CVC.p < 0.001)  . Covariates significantly associated at univariable level with type of vascular access, reported in After stepwise the covariates entered in the final model were: age class, BMI class, self-sufficiency, cardiovascular risk factors, heart disease, peripheral vascular disease, chronic obstructive pulmonary disease, cancer, type of dialysis center and early referral to nephrologist. p < 0.001)  . No sign2 (26.8%), not self-sufficient (35.3%), with an AVF as vascular access (25.7%) and without pre-dialysis counselling (19.1%). Results of univariable and adjusted OR for female to male mortality risk in incident HD patients are shown in It was found that OR and 95% confidence interval of 1-year mortality of females versus males moved from 1.08  to 0.84 (95% CI 0.74–0.96) overall after adjusting for age at incidence, BMI, self-sufficiency, and cause of ESRD. This result indicates that females have a slightly lower mortality risk than males at similar age, BMI, self-sufficiency and cause of ESRD, and this result was statistically significant.Subsequent adjustments for cancer, heart disease, peripheral vascular diseases, cardiovascular risk factors and laboratory findings  altered the female-to-male mortality risk only marginally, with the exception of the adjustment for type of vascular access, which significantly decreased the female-to-male mortality risk .The results of the sensitivity analysis, performed modifying the order of entry of the covariates, showed that the findings were consistent: adding adjustments for covariates showed a shift to the left  with a significant decrease after the adding of type of vascular access.p = 0.034). From stratified analyses by vascular access OR female vs. male = 0.65; 95%CI 0.48–0.87 in those with AVF and OR female vs. male = 0.88; 95%CI 0.75–1.04 in those with CVC were found. There was no evidence of interaction between gender and other independent covariates except for vascular access  with the gender gap in AVF use at initiation being highest in New York and the upper Midwest and smallest for Southern California and the Pacific Northwest and Alaska, suggesting variability related to cultural and organizing variables [The evidence of disparity in vascular access between genders is not novel. In 2002, Reddan et al. demonstrated that the likelihood of starting HD with a CVC was higher in women and that, in the multivariate analysis, female gender was one of the independent variables predictive of CVC in the final logistic regression model . Port etariables . The stuariables . In Euroariables . In 2020ariables .Overall, the reason of the differences in vascular access between men and women remains unclear. In general, AVF represents the best vascular access in HD and should be the first choice according to different guidelines ,37,38, dThe current study shows that females had a slightly lower mortality risk than males after adjustment for age, BMI, self-sufficiency and cause of ESRD, and this result was statistically significant. In addition, we observed a further reduction of mortality risk in females compared to males when considering only women who were offered AVF at HD initiation. Data on the effect of gender on mortality in incident patients are still conflicting. In some studies, gender was not a risk factor of one-year mortality ,44,45,46Sex-dependent differences are well established in several clinical conditions, especially in cardiology ,7. We evFurthermore, the higher survival rate characterizing females in the general population is markedly reduced in HD patients . Men conStrengths of this study are the large sample size and the integrated use of several Regional databases. These tools are subjected to continuous quality controlling that allow us to have accurate and standardized data. Generally, the epidemiological monitoring of CKD patients in Italy is relatively difficult because of the existing studies are related only to definite small areas and not to the entire country. Further potential confounders are probably the setting of the survey not allowing to collect accurate data, in particular a higher rate of response to survey was observed in the north versus the rest of Italy, in line with the higher economic and educational levels of this area . In LaziIn conclusion, the present prospective population-based cohort study in a large Italian Region shows that in women initiating HD, with respect to men, AVF was less common, and that one-year mortality was significantly lower. The identification of the mechanisms underlying these results requires further studies in the future. Nevertheless, the need for sex-specific treatment strategies in ESRD care is suggested.


Galectin-3, which is a novel biomarker of cardiovascular stress and related to inflammation, could predict adverse cardiovascular events. However, its relationship with endothelial function in patients with chronic kidney disease (CKD) remains inconclusive. This study aimed to investigate the association between serum galectin-3 levels and endothelial function in patients with stages 3–5 CKD. Fasting blood samples were obtained from 130 patients. Serum galectin-3 levels were determined using the enzyme-linked immunosorbent assay. The endothelial function, demonstrated as a vascular reactivity index (VRI), was measured noninvasively through digital thermal monitoring test. Then, we sorted the patients into poor, intermediate, and good vascular reactivity , accounting for 24 (18.5%), 44 (33.8%), and 62 (47.7%) patients, respectively. As the VRI decreased, the serum galectin-3 and C-reactive protein (CRP) levels significantly increased. The galectin-3 value positively correlated with the CRP value but negatively correlated with estimated glomerular filtration rate. In multivariable stepwise linear regression analysis, serum log-transformed galectin-3 level and log-transformed CRP were significantly negatively associated with VRI values. Therefore, galectin-3 together with CRP is associated with VRI values and is a potential endothelial function modulator and a valuable biomarker of endothelial dysfunction in patients with CKD. Over the past few decades, as the number of patients with chronic kidney disease (CKD) progressively increased, the number of adverse cardiovascular (CV) outcomes also increased; thus, multiple studies have been concentrating on interventions against cardiovascular disease (CVD) associated with traditional ,2,3 as wGalectin-3 is a novel 35 kDa, soluble β-galactoside-binding lectin expressed by epithelial cells, endothelial cells, and macrophages, with multiple biological abilities, including cell proliferation, differentiation, growth, and inflammation; it has also been related to cardiac fibrosis and heart failure and even long-term adverse prognosis of the general population  and patiMoreover, endothelial dysfunction is linked to adverse outcomes in patients with CKD ,25. Givep < 0.001) and C-reactive protein  significantly increased.Of the 130 patients with CKD, 24 (18.5%), 44 (33.8%), and 62 (47.7%) had poor, intermediate, and good vascular reactivity index (VRI), respectively . Age, ger = 0.239, p = 0.006) but negatively associated with eGFR  and VRI . Two-dimensional scattered plots of log-galectin-3 values with eGFR level, VRI, and serum log-CRP level among patients with CKD are presented as As the CKD stage progressed, the serum galectin-3 levels elevated a. In simr = −0.222, p = 0.011), creatinine , CRP , and galectin-3  negatively correlated with the VRI values  and serum galectin-3  were significantly and independently negatively associated with the VRI values . The levels of albumin, BUN, creatinine, fasting glucose, total cholesterol, triglycerides, low-density lipoprotein cholesterol, CRP, calcium, and phosphorus in their fasting blood samples were examined using an auto-analyzer . Moreover, we measured their serum galectin-3 concentrations by using a commercially available enzyme-linked immunosorbent assay . Body mass index was calculated as the weight in kilograms divided by the height in meters squared. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation . FurtherThe endothelial function of all participants was measured using an FDA-approved device  with DTM method, with BP cuffs and skin temperature sensors placed on both upper arms and index fingers, respectively ,33. In p2 test. Variables such as eGFR, VRI, and log-CRP, which correlated with log-galectin-3, were evaluated by simple linear regression analysis. Simple linear regression and multivariable stepwise linear regression analysis were applied to evaluate the association between VRI and clinical and biochemical variables. All statistical data were analyzed using the SPSS for Windows , and p values < 0.05 were considered statistically significant.Continuous variables were tested using the Kolmogorov–Smirnov test. Nonnormally distributed variables such as triglyceride, BUN, creatinine, CRP, and galectin-3 were then log-transformed. These variables, which are expressed as means ± standard deviation or medians with interquartile ranges (IQRs), were analyzed by Kruskal–Wallis analysis or one-way analysis of variance (ANOVA) accordingly. Categorical variables were expressed as the number of patients and analyzed by χ