Alveolar recruitment maneuvers enable easily reopening nonaerated lung regions via a transient elevation in transpulmonary pressure. To evaluate the effect of these maneuvers on respiratory resistance, we used an oscillatory technique during mechanical ventilation. This study was conducted to assess the effect of the alveolar recruitment maneuvers on respiratory resistance under routine anesthesia. We hypothesized that respiratory resistance at 5 Hz (R5) after the maneuver would be decreased after the lung aeration.2O for 15 s, including 5 s of gradually increasing the peak inspiratory pressure. Respiratory resistance was measured using the forced oscillation technique before and after the maneuver, and the mean R5 was calculated during the expiratory phase. The respiratory resistance and ventilator parameter results were analyzed using paired Student’s t-tests, and p < 0.05 was considered statistically significant.After receiving the ethics committee’s approval, we enrolled 33 patients who were classified with an American Society of Anesthesiologists physical status of 1, 2 or 3 and were undergoing general anesthesia for transurethral resection of a bladder tumor within a 12-month period from 2017 to 2018. The recruitment maneuver was performed 30 min after endotracheal intubation. The maneuver consisted of sustained manual inflation of the anesthesia reservoir bag to a peak inspiratory pressure of 40 cmH2O/L/sec before the recruitment maneuver during mechanical ventilation and was significantly decreased to 6.4 ± 1.7 cmH2O/L/sec after the maneuver. Peak inspiratory pressure and plateau pressure were significantly decreased, and pulmonary compliance was increased, although the values were not clinically relevant.We analyzed 31 patients (25 men and 6 women). R5 was 7.3 ± 1.6 cmHThe recruitment maneuver decreased respiratory resistance and increased lung compliance during mechanical ventilation.Name of registry: Japan Medical Association Center for Clinical Trials.Trial registration number: reference JMA-IIA00136.Date of registration: 2 September 2013.https://dbcentre3.jmacct.med.or.jp/JMACTR/App/JMACTRE02_04/JMACTRE02_04.aspx?kbn=3&seqno=3582URL of trial registry record:  Lung-protective ventilation using a low tidal volume is the standard of care for mechanically ventilated patients with acute respiratory distress syndrome  and was The forced oscillation technique (FOT) is used to measure respiratory impedance by measuring the relationship between pressure waves applied externally to the respiratory system and the resulting respiratory airflow. The FOT device measures respiratory resistance at 5 Hz (R5), which includes the resistance in the oropharynx, larynx, trachea, bronchi, pulmonary alveolus, and chest wall tissue. Exertional breathing maneuvers are not required during FOT measurement. MostGraph-01®  is a noninvasive device that measures respiratory resistance using broadband frequency FOT. We previously reported using this device to measure increased respiratory resistance after general anesthesia –21.2), respiratory resistance would be a better parameter for detecting the effects of ARMs in patients with mostly intact respiratory systems. This study was conducted to assess the effect of ARMs on respiratory resistance during routine anesthesia. We hypothesized that the R5 would be decreased after the ARM because of the lung aeration and that the tidal volume would be increased, even under volume-controlled ventilation.Because few studies have evaluated ARMs independently of the PEEP level, we investigated the effect of ARMs on respiratory status during surgery. We hypothesized that compared with respiratory compliance, tidal volume and partial pressure of oxygen in the arterial blood  approved the study, which was conducted in accordance with the declaration of Helsinki (1964). All participants provided written informed consent. The study was registered at the Japan Medical Association Center for Clinical Trials (reference JMA-IIA00136). We enrolled 33 patients who were classified as American Society of Anesthesiologists physical status 1, 2 or 3 and undergoing general anesthesia for transurethral resection of a bladder tumor within a 12-month period from 2017 to 2018. Exclusion criteria included substantive abnormalities in spirometry , active asthma (requiring bronchodilator therapy or coughing or wheezing at rest), preoperative fractional nitric oxide concentration in exhaled breath (FeNO) > 50 ppb , previouRespiratory examinations were performed, including spirometry without bronchodilation and FeNO measurement. Spirometry was performed within a month before surgery using a spirometer  and FeNO was measured using NIOX VERO®  the day before surgery. Respiratory resistance was measured using the MostGraph-01® the day before and the day after surgery. Patients sat with a nose clip and their cheeks supported firmly during the respiratory resistance measurements.A standardized anesthetic technique was used. Anesthesia was induced with 1.0–1.5 mg/kg intravenous propofol, 0.7–0.9 mg/kg rocuronium, a continuous infusion of 0.4 μg/kg/min remifentanil and 2.0–3.0% inhaled sevoflurane. The trachea was intubated with a tube that had an internal diameter of 7.0 mm for women and 8.0 mm for men . Anesthesia was maintained with inhaled sevoflurane, intravenous remifentanil and intravenous rocuronium at 4–6 μg/kg/min. The sevoflurane concentration was titrated over 1.5% at the discretion of the attending anesthetist according to a bispectral index monitor that was controlled between 40 and 60. At the end of the surgery, patients were administered 1000 mg intravenous acetaminophen for pain relief, followed by 1.5–2.0 mg/kg (maximum 200 mg) intravenous sugammadex. Tracheal suctioning was performed once or twice before patients were extubated. The endotracheal tube was removed when patients could communicate and breathe spontaneously with sufficient tidal volume. Supplementary oxygen at 6 L/min was administered via facemask immediately after extubation.2O, a respiratory frequency of 10–12 breaths/min to maintain the end-tidal carbon dioxide from 35 to 45 mmHg, and an oxygen inspiratory fraction of 0.4 . The ARM was performed 30 min after tracheal intubation and consisted of sustained manual inflation of the anesthesia reservoir bag to a peak inspiratory pressure of 40 cmH2O for 15 s, including gradually increasing the peak inspiratory pressure for 5 s. Before the ARM, the peak airway pressure, plateau pressure, PEEP, and tidal volume were obtained from the ventilation monitor. Dynamic respiratory compliance (Cdyn) and static pulmonary compliance (Cst) were calculated as Cdyn = tidal volume/(peak pressure − PEEP) and Cst = tidal volume/(plateau − PEEP).After inducing anesthesia, all patients were mechanically ventilated using the volume-controlled mode with an inspiratory/expiratory ratio of 1:2, an inspiratory pause time/total inspiratory time ratio of 0.1, tidal volume of 8 mL/kg ideal body weight with a PEEP of 5 cmHWe modified this device to measure the R5 during ventilation using an endotracheal tube under general anesthesia. We used the MostGraph-01®, which was modified to measure respiratory resistance during mechanical ventilation Figs.  as previ2O/L/s (mean ± SD) and 4.88 ± 1.35 cm H2O/L/s, respectively; therefore, the standard deviation was considered to be 1.25, and the expected difference in R5 was considered to be 1.25 cm H2O/L/sec. The sample size was determined from our preliminary R5 study of 8 patients using a subglottic airway device. A sample size of 33 patients was required to obtain 80% power between the pre-ARM and post-ARM at an α error level of 5% and an intragroup difference of 1.25 cm H2O/L/s in R5. Data are expressed as the mean ± SD or median  according to the variable distribution. Normality was analyzed using the Shapiro-Wilk test. The MostGraph-01® and ventilator parameter results were analyzed using paired Student’s t-tests; p < 0.05 was considered statistically significant. All statistical analyses were performed using GraphPad Prism 6 software .Our preliminary measurements for the pre-ARM R5 and post-ARM R5 were 5.49 ± 1.25 cm H2O/L/sec; the postoperative R5 was 2.8 ± 0.9 cmH2O/L/sec.For two of the 33 patients, the respiratory resistance measurement during mechanical ventilation was saved incorrectly; therefore, 31 patients (25 men and 6 women) were included in the final analysis. No patients experienced any serious perioperative events. No patient showed a preoperative FeNO > 50 ppb. No patient had < 96% oxygen saturation as measured by pulse oximetry. Table 2O/L/sec after the maneuver. Peak inspiratory airway pressure and plateau pressure were significantly decreased. Pre- and post-ARM lung compliance (Cdyn) were 47.0 ± 8.8 mL/cmH2O and 50.0 ± 8.9 mL/cmH2O, respectively. Pre- and post-ARM Cst were 58.3 ± 13.9 mL/cmH2O and 63.1 ± 13.3 mL/cmH2O, respectively. Lung compliance significantly increased after the ARM. Post-ARM tidal volume on the ventilator measurement was significantly increased compared with the pre-ARM tidal volume but not on the MostGraph measurement.R5 was significantly decreased after the post-ARM during mechanical ventilation Table . The R5 This was the first study to evaluate the effect of ARMs on respiratory resistance. R5 represents respiratory resistance, including resistance in the oropharynx, larynx, trachea, bronchi, lungs, and chest wall tissue. This study showed that ARMS improved the R5 under general anesthesia, increased the lung compliance, and reduced the peak and plateau pressures. An increase in lung compliance immediately after applying the ARM might reflect a reduced atelectasis. A decrease in R5 suggests an improved Cdyn. Although the effect of ARMs on lung compliance is controversial , many st2O for 30 s [2O for 7–8 s effectively opened all alveoli in a nonobese patient with healthy lungs [2O for 10 s in this study, primarily to prevent significant hemodynamic changes. ARM refers to a transient increase in transpulmonary pressure induced by increased intrathoracic pressure and decreased venous return, leading to a decrease in left ventricular end-diastolic areas and stroke volume [A 2006 multicenter observational study in France reported that ARMs were only used in 7% of patients ; howeverfor 30 s . A studyhy lungs . We usede volume , 28. Impe volume .Contemporary anesthetic ventilators often include options to display the pressure-volume loop and calculated dynamic compliance values. Comparing the pre- and post-ARM lung compliance enables easier detection of the ARM’s effectiveness . AutomatSome studies have reported beneficial effects from ARMs. A randomized controlled trial revealed fewer incidences of postoperative nausea and vomiting after gynecological laparoscopic surgery . Additio2O) prevents it (Fig. This study had some limitations. This was the first study to detect respiratory resistance during mechanical ventilation using the MostGraph-01®. We followed previously described methods to measure the respiratory resistance through an endotracheal tube . There w it Fig. . This deAnother limitation was that PEEP was not applied when measuring respiratory resistance using the MostGraph-01® because adding a positive expiratory pressure made it difficult to detect respiratory resistance. In normal clinical situations, PEEP is needed directly after ARMs to prevent lung collapse; therefore, a better technique is required.2 to evaluate the effect of the ARMs. We could not perform blood gas analyses during the transurethral resection surgeries performed during this study. This surgery was chosen to prevent the influence of respiratory status under well-controlled anesthesia. We showed that respiratory resistance was statistically significant but could not show its clinical relevance. A new study, including clinical parameters, is needed.We did not measure PaOThe ARM decreased respiratory resistance and increased lung compliance during mechanical ventilation. The ARM caused the airways to reopen. Although some difficulties were noted, measuring the FOT using the MostGraph-01® is a straightforward method to evaluate changes in respiratory resistance. We showed that respiratory resistance was statistically significant but could not show its clinical relevance. This measurement may help determine the best ARM type for patients under general anesthesia.


CPET significant threshold values in identifying a left ventricular ejection fraction (LVEF) < 39% were: 1) OUES: < 1.3; 2) CP < 2116 mmHg.mlO2.kg−1.min−1 and minute ventilation/carbon dioxide production (V̇E/V̇CO2) slope>38. The 15 (38%) patients hospitalized during follow-up (8 ± 2 months). In the hospitalizations analysis, LVEF < 39% and FEV1 < 1.6, OUES < 1.3, CP < 2116 mmHg.mlO2.kg−1.min−1 and V̇E/V̇CO2 > 38 were a strong risk predictor for hospitalization (P ≤ 0.050). The CPET response effectively identified worsening disease severity in patients with a HF-COPD phenotype. LVEF, FEV1, CP, OUES, and the V̇E/V̇CO2 slope may be particularly useful in the clinical assessment and strong risk predictor for hospitalization.Our aim was to identify optimal cardiopulmonary exercise testing (CPET) threshold values that distinguish disease severity progression in patients with co-existing systolic heart failure (HF) and chronic obstructive pulmonary disease (COPD), and to evaluate the impact of the cut-off determined on the prognosis of hospitalizations. We evaluated 40 patients (30 men and 10 woman) with HF and COPD through pulmonary function testing, doppler echocardiography and maximal incremental CPET on a cycle ergometer. Several significant CPET threshold values were identified in detecting a forced expiratory volume in 1 second (FEV COPD overlap syndrome in HF can reach up to 30%4. The prevalence of COPD in patients hospitalized for HF is 10%, and the risk of developing HF during hospitalization due to COPD decompensation is 4.5%5. These diseases also have relevant systemic components that affect widely the musculoskeletal system8 in addition to the heart and lungs.Chronic obstructive pulmonary disease (COPD) and heart failure (HF) coexist not because of their high individual prevalence, but because both share common etiological and pathophysiological factors, such as smoking and systemic inflammation10. This varies considerably in patients with HF-COPD with pulmonary involvement [Forced Expiratory Volume in the first second (FEV1)] and cardiac [left ventricular ejection fraction (LVEF)]13. However, the structural and physiological determinants that support this great variability remain poorly understood. It is not clear the impact of FEV1 and LVEF on cardiorespiratory and metabolic variables within cardiopulmonary exercise testing (CPET) in HF-COPD patients.There is an increasing recognition that exercise intolerance in overlap of HF-COPD cases may be associated with increased ventilatory responses due to metabolic demand, resulting in ventilatory inefficiency14. In addition, variables such as peak oxygen uptake (V̇O2), the product of peak ventilation (V̇E) and carbon dioxide production (V̇E/V̇CO2 slope)15 are important cardiac prognostic indices13. Guazzi et al. (2013) showed that the peak of V̇O2 < 10 mL/kg/min and V̇E/V̇CO2 slope ≥45 were independent predictors of long-term mortality in HF and COPD15. O2 pulse, circulatory and ventilatory power  are related to predictors of mortality in all chronic heart failure patients18.CPET is the gold standard and established tool to assess functional capacity and to determine prognosis in HF and COPD patients20. Thus, there is no information about the impact of HF-COPD on CPET variables, since these patients have marked ventilatory and cardiac limitations and, from a clinical point of view, established cut-off values for these patients based on the disease severity. It would be of utmost importance to determine during the performance of CPET, the clinical condition, diagnosis and best prescription of cut-off training for these patients.In addition, the studies that performed CPET focused on the variation between different populations presented as main objective the comparison with tests1 < 1.6 and LVEF < 39%.Our aim was to identify optimal CPET threshold values that distinguish disease severity progression in patients with co-existing systolic HF and COPD. Our secondary aim was to evaluate the impact of the cut-off determined on the prognosis of hospitalizations of these patients. We hypothesize that CPET variables are important prognostic determinants for cardiorespiratory worsening in patients with FEVThis cross-sectional study was designed following the recommendations of the STROBE statement. All patients were recruited from the Cardiology and Pulmonology outpatient clinic of São Carlos. The study followed the Declaration of Helsinki and was approved by the local ethics committees  (protocol number: 91088318.7.1001.5504). All volunteers signed a written informed consent statement prior to participation.1/forced vital capacity (FVC) ratio of 0.7; FEV1 60% of predicted] without previous COPD exacerbation (3 months before the study) and clinical diagnosis of HF from a cardiologist with ejection fraction (<50% by echocardiogram), without cognitive impairment or comprehension deficiencies, older than 50 years of age and with HF class I, II or III according to the New York Heart Association Functional Classification (NYHA) were included in the study16.51 patients with clinical diagnosis of COPD by pulmonary function test ); (II) general/leg fatigue or dyspnea; (III) angina or electrocardiographic evidence of ischemia or malignance arrhythmia ; or (IV) inability to maintain a pedaling rate of 60 rpm for 30 seconds.V̇O2 (ml/kg/min), V̇CO2 (ml/min), V̇E/V̇CO2 slope21, workload (WR) (watts), HR peak (bpm) and V̇O2 efficiency slope (OUES)22. O2 pulse was calculated using the product of peak V̇O2 and peak HR. CP was calculated using the product of peak V̇O2 and peak SBP17. VP was obtained by dividing peak SBP by the V̇E/V̇CO2 slope21. V̇O2/WR was determined by the relationship between maximal workload obtained and V̇O2 peak23.During CPET the following parameters were measured: peak systolic and diastolic blood pressure (SBP and DBP) (mmHg), peak 1.Patients were included and accompanied during 12 months by telephone calls to their home or family physician. The hospitalizations were determined when the patient was hospitalized for more than one day, our patients had the following hospitalizations: COPD exacerbations (type II and III) (n = 6), HF decompensation (n = 5) and myocardial revascularization (n = 4). COPD exacerbations are classified as: type II - increased medication and medical intervention; and type III - worsening of the clinical condition requiring hospitalizationThe Shapiro-Wilk test was used to verify the data distribution. Descriptive data was shown as a mean, standard deviation and frequency. The parametric Student’s t-test was used for normally distributed data. Pearson correlation analysis were performed to investigate the relationship between variables. All tests were made in Statistical Package for the Social Sciences (SPSS) and values were accepted as P ≤ 0.05.1 (L) and the severity of HF considering LVEF (%). Cut-off points discriminated the precision of CPET variables: VP, CP, O2 pulse, OUES, V̇E/V̇CO2 slope and V̇O2 peak in determining points of predictive cut-off in HF-COPD. The confidence interval (95% CI) was used to determine the ability of the clinical variables, with the lower limit being greater than 0.50. Subsequently, the cut-off points of the variables that obtained significant areas under the ROC curve were identified, with the respective values of sensitivity and specificity.First, receiver operating characteristic (ROC) curve analyses selected the optimal threshold values to differentiate the severity of COPD considering FEV1 < 1.6 and LVEF < 39%, CP < 2338, VE/VCO2>38 and OUES>1.3. Differences between curves were evaluated using the log-rank test.We examined all hospitalization that occurred during the 12-months follow-up. Hospitalization curves were analyzed according to the Kaplan-Meier method to explore the impact of FEVWe initially included 51 HF-COPD patients, however due to our exclusion criteria, 11 patients did not participate in the study protocol: 1 was excluded for brain cancer, 7 did not agree to participate in the study, 1 due to aortic aneurysm, and 2 due to encephalic vascular accident. Therefore the protocol was carried out with 40 HF-COPD patients.Table 1 < 1.6 L [11 (71%)] and presented reduced O2 pulse when compared with non-hospitalized (p < 0.05).During follow-up 10 ± 2 months), 15 patients were hospitalized (7 ± 2 months) and 25 were not hospitalized (10 ± 1 months). Table  months, vs LVEF  and FEV1 vs V̇O2/WR , suggesting that the worse the airway obstruction and LVEF, the worse the behavior of these variables in CPET, thus compromising the performance of these HF-COPD patients.We found significant correlations between: OUES 1 < 1.6 L [n = 21 (52%)] and LVEF < 39% [19 (n = 48%)], our aim in performing this stratification is to demonstrate the impact of diseases on CPET variables and may assist in clinical practice.From this point of the study, our results will be divided by the mean found in our patients FEV2.min−1 identified as cut-off points for HF- COPD patients with FEV1 < 1.6 L.The cut-off points, the areas under the ROC curve and 95% CI, as well as the sensitivity and specificity of the clinical variables are shown in Table 2.kg−1.min−1 and V̇E/V̇CO2 slope > 38 identified as cut-off points for HF-COPD patients with LVEF < 39% . In the analysis for the CPET variables, we found that only V̇E/V̇CO2 > 38, OUES < 1.3 and CP < 2383 mmHg.mlO2.min−1 were prognostic indicators for hospitalization (P ≤ 0.05) in COPD-HF patients  and ventilatory equivalent oxygen (OUES); II) OUES < 1.3 and CP < 2383 mmHg.mlO2.kg−1.min−1 were identified as cut-off points for HF-COPD patients with FEV1 < 1.6 L; III) OUES < 1.3, CP < 2116 mmHg.mlO2.min−1 and V̇E/V̇CO2 slope > 38 were identified as cut-off points for HF-COPD patients with LVEF < 39%; IV) In Kaplan-Meier analysis: LVEF < 39% and FEV1 < 1.6, V̇E/V̇CO2> 38, OUES < 1.3 and CP < 2383 mmHg.mlO2.min−1 were prognostic indicators for hospitalization in COPD-HF patients.This is the first study to identify relative cut-off scores to determine prognostic markers of cardiorespiratory worsening and hospitalization in patients through variables of CPET based on COPD and HF severity. The main findings of the present study were: I) Correlations suggest that worsening airway obstruction and LVEF, directly impact in aerobic function , as well as the prognosis value of cardiopulmonary exercise testing to help healthcare professionals to identify potential patients for hospitalization. It is possible with cut-off values to obtain a response about the patient’s general health, as we know that hospitalizations limit or even preclude rehabilitation and may aggravate the exercise intolerance of this population.33.The main limitation in our study is the small number of COPD-HF coexistence, however, despite the high prevalence of COPD and HF, such coexistence has been poorly studied, especially considering the impact of disease severity on exercise capacity. In this sense, future studies should be conducted with a larger sample to confirm our findingsV̇E/V̇CO2 slope) and predictors of hospitalization for HF-COPD patients with FEV1 < 1.6 L and LVEF 39%. Thus, this is the first study to investigate these indices in HF-COPD patients based on the severity of the diseases. We emphasize as a limitation the sample size, however it is known the difficulty in screening COPD-HF coexistence and that so far no follow-up studies and prognosis of hospitalizations in this population have been conducted, thus highlighting the importance of this work.The strengths of our study include the novelty of finding cut-offs for new rates (CP, OUES and V̇E/V̇CO2 slope provided to be useful in practice to clinical interpretation of cardiopulmonary responses during exercise and are a strong risk predictor for hospitalization in HF-COPD coexistence patients.In conclusion, heart failure with reduced left ventricular ejection fraction as well as the severity of COPD impacted negatively selected physiological responses obtained by CPET. CP, OUES and


Allergic rhinitis (AR) and asthma are the most common allergic disorders worldwide. Aeroallergens are critical causative factors in the pathogenesis of these disorders and sensitization to aeroallergens differs in various countries and regions. Identification of the most common aeroallergen sensitization is crucial in the diagnosis and management of AR and asthma. We examined the distribution of aeroallergen sensitizations detected by skin prick tests (SPTs) in adult patients with AR and/or asthma in the city of Bursa.  Five hundred forty-five patients who underwent a SPT and were diagnosed with rhinitis and/or asthma in the Uludağ University Faculty of Medicine’s Department of Immunology and Allergic Diseases Outpatient Clinic from March 2018 to August 2018 were retrospectively evaluated. SPTs with standard extracts including house dust mites, pollens, molds, animal dander, and latex were performed for patients.Dermatophagoides farinae (50%) and D. pteronyssinus (44%), followed by grass-rye mix (43%), grass mix (38.6%), olive (33.2%), and wheat (32.3%). The sensitization to olive pollen was higher in cases of mild asthma (52%), while sensitization to D. farinae was higher in patients with mild and moderate asthma  (P < 0.05). A total of 545 patients were included and most of the patients  were between 30 and 49 years of age. The prevalence of atopy was 57.9%. The most common aeroallergens detected in SPTs were Our study revealed that house dust mite was the most common sensitizing aeroallergen in patients with AR and asthma while pollens were the most common allergen in patients with only AR. The sensitization to grass and olive pollen was higher in cases of mild asthma than moderate and severe. Regional allergy panels may provide important clinical clues for characteristics and courses of allergic diseases. The prevalence of allergic rhinitis (AR) and asthma has risen significantly over the last two decades [1]. Prevalence of respiratory allergies  was documented as 12%–20% worldwide [2]. AR is the most common atopic disease and affects more than 500 million people around the world [3]. Furthermore, 300 million people worldwide suffer from asthma, and it is projected to increase to 400 million by the year 2025 [4]. In particular, increasing industrialization and air pollution are considered as leading causes of the high prevalence of AR and asthma .The etiologies of AR and asthma are complex, resulting from genetics  and interacting environmental factors . Allergic sensitization to aeroallergens is a major risk factor for developing an allergic disease and optimal management of allergic diseases requires the identification of the allergic sensitivities of the patient [11]. The common allergens include house dust mites (HDMs), grasses, trees, weed pollens, animal dander, and molds [5].Turkey is a bridge between Europe and Asia, surrounded by the Marmara Sea, Black Sea, and Mediterranean Sea on three sides. In Turkey, the prevalence of AR and asthma varies between 11.4% and 22.7% and between 2% and 17%, respectively, in adult patients based on regional prevalence . Depending on the considerable variety of climates, aeroallergen spectra and disease prevalence rates differ in distinct regions of Turkey. There is only one study that revealed the aeroallergen sensitivity of patients with asthma in Bursa. Bursa is located to the southeast of the Marmara Sea in Northwest Turkey [18] at an altitude of 100 m above sea level, with average relative humidity of 69%. Because the humidity rate of Bursa Province is above 50%, it facilitates the growth of mites in indoor environments. Avoiding exposure to an allergen is the best way to prevent the disease. Our study aims to find the prevalence of various allergens leading to AR and/or asthma through skin prick tests (SPTs) in the city of Bursa, Turkey.This retrospective clinical study was conducted in the Department of Immunology and Allergic Diseases, Uludağ University Medical Faculty Hospital, Bursa, Turkey. The study was approved by the institutional ethics committee of Uludağ University (identification 2019/20).The medical records of 545 adult patients who were diagnosed with rhinitis and/or asthma and lived in Bursa were analyzed. AR and asthma were diagnosed and classified based on the Allergic Rhinitis and Their Impacts on Asthma (ARIA) and the Global Initiative for Asthma (GINA) guidelines, respectively. Asthma severity was classified as mild/moderate/severe according to medication use with level of treatment as defined in GINA as mild (steps 1–2), moderate (step 3), and severe (steps 4–5) [19]. We reviewed the medical records of all patients who presented to our department from March 2018 to August 2018.Dermatophagoides pteronyssinus, D. farinae, Acarus siro, Fusarium, Alternaria, cockroach). SPT was performed according to the international guidelines as a single test on two forearms with lancets and standardized allergens by the same trained nurse. Histamine hydrochloride (10 mg/mL) and 0.9% saline were applied as positive and negative controls, respectively. The wheel diameter was measured after 20 min and reported in mm. A skin reaction of at least 3 mm greater than that produced by the negative control in the SPT was considered as a positive reaction.The SPT was conducted using a standard commercial extract panel , consisting of 17 aeroallergens . Chi-square tests, independent t-tests, and Mann–Whitney U tests were used to examine and compare the relationship between the characteristics of the sample. P < 0.05 was considered statistically significant.A total of 545 patients  were enrolled in this study. The median age was 41 years (range: 18–82). Most of the patients  were in the age group of 30–49 years (Table). Three hundred sixteen of the patients (57.9%) were found to be sensitized to at least one of the 17 aeroallergen extracts tested. One hundred sixty-seven of the sensitized patients (52.8%) had AR without asthma, 135 of the sensitized patients (42.7%) had AR with asthma, and 14 of the sensitized patients (4%) had only asthma.D. farinae 50%; D. pteronyssinus 44%), followed by grass-rye mix (43%), grass mix (38.6%), olive (33.2%), wheat pollen (32.3%), storage mite (Acarus siro 26.3%), tree pollens (23.7%), weed pollen (22.5%), birch pollen (22.2%), oak (20.3%), cockroach (19.9%), Fusarium (14.6%), dog (12.7%), cat (12%), Alternaria (12%), and latex (10.8%) .The most frequent aeroallergens that we determined in the SPTs were mites . No significant difference was observed between the sexes for the remaining allergens. We classified patients into three groups according to age cutoff points commonly used in the medical literature: 18–29, 30–49, and 50+ years old. There was a significant difference among these groups for grass-rye mix, grass mix, and wheat allergen sensitivity rates. The sensitization rates to the grass-rye mix were 32.4%, 55.1%, and 12.5% for subjects of 18–29 years, 30–49 years, and 50+ years, respectively. We found a significant association between sensitization to grass-rye mix and the age groups of the subjects (P = 0.001). The sensitization rates against grass were higher in the group of 30–49 years (53.3%) than 18–29 years (33.6%) and 50+ years (13.1%) (P = 0.001). The prevalence of sensitization to wheat was also higher in the group of 30–49 years (55.9%) than 18–29 years (33.3%) and 50+ (10.8%) (P = 0.001).D. pteronyssinus 52.6%; D. farinae 51.3%), followed by grass-rye mix (41.5%), grass mix (38.5%), olive pollen (31.1%), storage mites (28.1%), wheat pollen (28.1%), cat (11.2%), and dog (14.1%).In asthma patients with AR, the most frequent aeroallergens were mites , grass mix (39.5%), olive pollen (36.5%), wheat pollen (36.5%), weed pollen (25.1%), and storage mites (25.1%). Latex (8.4%) and Alternaria (9%) were rare.In patients with only AR, the most frequent aeroallergen was grass-rye mix (52.8%), followed by mites (D. farinae (21.4%), wheat pollen (21.4%), and tree pollen (21.4%). Cat, latex, and Alternaria sensitizations were not seen (0%) .In patients with only asthma, the most frequent aeroallergens were grass mix (28.6%), birch (28.6%), oak (28.6%), and cockroach (28.6%), followed by grass-rye mix (21.4%), storage mites (21.4%), D. farinae) and asthma severity. The sensitization rates to the grass-rye mix were 36%, 58.8%, and 29.8% for subjects with mild, moderate, and severe asthma, respectively. The sensitization rates against grass were higher in cases of mild asthma (60%) than moderate (52.9%) and severe (29.8%) (P = 0.01). The sensitization to olive pollen was higher in cases of mild asthma (52%), while sensitization to D. farinae was higher in patients with mild and moderate asthma  (P = 0.04) .Our study showed an association between sensitization to four aeroallergens , followed by pollen , storage mites (26.3%), cockroach (19.9%), molds , and epithelia . There is remarkable variability in aeroallergen distribution among countries, and even among regions within the same country [4]. In general, HDM sensitization is more common in tropical countries such as Malaysia and Singapore [22]. However, pollens are the most sensitizing aeroallergens in Europe [23]. Allergic sensitization to mites has been studied in different regions of Turkey. Studies in Turkey have reported sensitization rates to D. pteronyssinus and D. farinae as 72.5% and 63.7% in Düzce [24], 62.2% and 51.3% in Eskişehir [25], 25.3% and 29.3% in İstanbul [26], and 22.4% and 21.5% in Isparta [27]. A previous study that included various regions of Turkey showed that the presence of mites was related to an increase in both mean temperature (>15 °C) and humidity (³40%), as well as low altitude (<300 m) [28]. In our study, high sensitization to HDMs was expected due to the regional geography with 69% humidity and a location at an altitude of 100 m above sea level.In our study, 316 patients had a positive reaction to the SPT. HDMs were the most prevalent sensitizing aeroallergens (Our study showed more prevalent sensitivity to grass-rye mixes, weeds, olive pollen, and cats among women. Conversely, other studies from Kuwait and China showed a higher prevalence rate of sensitization towards outdoor allergens in males . No convincing clarifications have been given for these differences between the sexes. There is no evidence to suggest that sex leads to differential exposure to aeroallergens [29].D. microceras, which had a higher prevalence rate in the 45+ years age group [29]. Other studies from Turkey and other countries found no difference in the prevalence of positive SPT between younger and older patients with AR .Looking at the age distribution of the allergen groups, sensitization to grass-rye, grass, and wheat were seen more frequently in patients between 30 and 49 years. We found no difference in sensitization to other aeroallergens according to age groups. A previous study from Kuwait indicated age-dependent sensitization to the HDM HDM sensitization associated with the risk of rhinitis and asthma in children and adults has been shown by several researchers . Allergic responses to HDM are associated with airway hyperresponsiveness and it is the most important indoor allergen for asthma [34–37]. A previous study from Bursa and other studies showed high sensitization to HDM in asthma patients . In accordance with the literature, we found high HDM sensitivity in asthmatic patients. Related to the regional geography with high humidity and temperature, sensitization to indoor allergens was expected.D. farinae sensitization was higher in cases of mild and moderate asthma. Grass-rye sensitization was higher in cases of moderate asthma. A study from Kuwait indicated a high frequency of severe asthma in patients sensitized to Cladosporium, Aspergillus, and Alternaria. A study from Saudi Arabia showed higher asthma severity correlation with the degree of sensitization to D. pteronyssinus and D. farinae.Looking at the association between asthma severity and allergen sensitivity, olive and grass sensitization was higher in cases of mild asthma. It is known that 24.4% of olive trees in Turkey are located in the Marmara region, and 37.4% of the olive trees in the Marmara region are in Bursa. In addition, the most commonly grown fruit in the province is olive [39]. Therefore, sensitization to olive tree is expected. For patients with only AR, the most frequent aeroallergen was the grass-rye mix, followed by mites, grass mix, and olive. In this regard, our results are consistent with some previous studies, which indicated grass pollens as the most common allergen in patients with AR . On the other hand, some previous studies from many countries showed that HDMs were common aeroallergens in patients with AR . This appears to be a geographical variation. Our findings correlated with the climate of Bursa, which is characterized by dry and warm summers and wet and cold winters. The climate in Bursa allows many plants to grow, flower, and produce and release pollen grains into the atmosphere at any time of the year. The number of pollen grains increases from February to April and reaches its maximum level in May [21]. Grass pollen, which is the most dominant aeroallergen in May and June, causes great problems for individuals with pollen allergies .In conclusion, the most frequent aeroallergen that we determined in the SPT was mites, followed by pollens, cockroach, mold, animal dander, and latex. Our study showed high HDM sensitization in patients with asthma and AR; on the other hand, sensitization to pollens was most common in patients with only AR. Furthermore, olive-sensitive patients had mild asthma, and mite-sensitive patients had mild to moderate severity. Identification of allergens is an essential step in the diagnosis of respiratory allergic disease. Specific allergy panels based on regional differences in patterns of sensitization can provide cost-effective screening of sensitized patients and better management of the disease with environmental allergen control.The authors would like to thank allergy clinic nurses Meral İnal and Mürüvvet Canık for performing and archiving the skin prick tests.


Different drugs used to treat asthma, such as beta 2 agonists and inhaled steroids, may promote a higher risk of caries, dental erosion, periodontal disease and oral candidiasis. This article reviews the evidences of mechanisms involved in oral diseases in patients affected by asthma. The main mechanism involved is the reduction of salivary flow. Other mechanisms include: acid pH in oral cavity induced by inhaled drugs , lifestyle , gastroesophageal reflux, and the impairment of local immunity. In conclusion asthma is involved in the genesis of oral pathologies both directly and indirectly due to the effect of the drugs used to treat them. Other cofactors such as poor oral hygiene increase the risk of developing oral diseases in these patients. Preventive oral measures, therefore, should be part of a global care for patients suffering from asthma. Asthma is a chronic inflammatory disease characterized by increased airway responsiveness to various environmental triggers and by symptoms such as wheezing, coughing, chest tightness and dyspnoea. The diagnosis is based on clinical evaluation and functional demonstration of reversible airway obstruction, either spontaneously or after medical treatment . DiffereAsthma is a growing health problem affecting over 300 million people worldwide. The recent Global Strategy for Asthma Management and Prevention Report shows that 15% of Italian children suffer from wheezing and 11.6% from lifetime asthma. For adults, these percentages decrease to 6% and 10% respectively and women result more affected by wheezing than men: 6.64% versus 5.49%. Women also have a peak prevalence between the ages of 45 and 55 years old. Otherwise, the disease tends to decrease in old age [The aim of asthma treatment is to reduce airways inflammation and to induce bronchodilation in order to control symptoms and prevent the progression of the disease and the onset of exacerbations . TreatmeMany inhaled drugs used to treat asthma may have systemic effects.Inhaled corticosteroids systemic effects impact on the hypothalamo-pituitary-adrenal (HPA) axis, as well as on bones, skin, eyes, growth and immunity. Systemic effects are dose-related and their relevance depends on patient’s susceptibility regardless of steroid type. However different molecules are associated with differently relevant side effects, being budesonide responsible for a few systemic effects whilst fluticasone having a higher risk especially at doses above 400 mcg/day [ mcg/day . In asth mcg/day .Inhaled beta2-agonists at high dose also cause dose-related systemic adverse effects including tremor, tachycardia, hypokalaemia and are associated to electrocardiographic sequelae, which are mediated by extrapulmonary receptors. Systemic absorption occurs primarily across the lung-vascular bed and hence compounds which are more lipophilic, such as fenoterol, are absorbed to a greater extent [r extent .Inhaled anticholinergics (ex. tiotropium) can cause side systemic effects that include cardiac events such as tachycardia and gastrointestinal involvement such as constipation, as well as urinary retention and urinary tract infections. Concerning tiotropium (the only anticholinergic drug approved in severe asthma) it has been reported in asthmatic adults and in children that there were low or absent systemic side effects in all age groups [e groups .At the same time, these drugs can have local effects being involved in oral disease through different pathways, promoting a higher risk of caries, dental erosion, tooth loss, periodontal disease and oral candidiasis . FurtherSaliva is composed of water and a range of inorganic and organic components, which allow oral protection from micro-organisms, lubrication for mastication, and protection for tooth structures .The physiological functions of the saliva are to supply nourishment to the oral microbiota, to carry antimicrobial factors, and to contribute to the maintenance of microbial homeostasis .Over 700 different bacterial species have been identified in the oral microbiota , 11. FirSalivary flow and composition play a fundamental role in oral health, with a defensive mechanism that can be impaired in the asthmatic condition due to medications used and alimentary habits or lifestyles .Saliva is involved in maintaining a neutral pH in the oral cavity sometimes reaching values up to 7.67 depending on different types of buffering systems such as bicarbonate, phosphate, urea, and amino peptides . SalivarThree studies conducted between 1991 and 1998 about the effect of beta 2 short acting agonists, taken over a period of 7 days, reported no reduction in salivary flow. A study of 15 patients with moderate persistent asthma treated with salmeterol 50 mcg plus fluticasone propionate 100 mcg twice daily, for 1 month, demonstrated a reduction in salivary flow rate associated to an increase in dental plaque index and no modification in salivary IgA . In anot® trial reported that there were no evidence of dry mouth in patients treated with LABA [Recently, tiotropium  has been approved as an add-on controller medication in patients with severe asthma . Xerostoith LABA . In concith LABA .The reduced salivary flow could result in lower antimicrobial protection and oral dehydration of the mucosa so that, in order to prevent xerostomia, these patients intake a large amount of products that could be cariogenic. In fact, an increasing consumption of drinks that have low pH was noted and could be involved in erosive lesions. Lifestyle choices of asthmatic children, with frequent consumption of sweets, could also promote oral lesions .Furthermore, the inhaled therapy is often taken at night before going to bed without any oral hygiene and the lack of masticatory movements might increase the damage in the oral environment due to the medications themselves .Inhaled steroids play a central role in asthma treatment due to their anti-inflammatory effect  and theiOropharyngeal candidiasis is common in people using nebulized corticosteroids , with a A study conducted in Japan in 2003 enrolled 143 asthmatics under treatment with inhaled steroids , 11 asthmatics patients not treated with CSI and 86 healthy controls. The data confirmed that a larger amount of Candida spp. organism was detected in asthmatic patients treated with CSI (p < 0.001). The aim of the study was also to evaluate the incidence of oral candidiasis in patients treated with fluticasone propionate through a dry powder inhaler rather than in patients treated with beclomethasone dipropionate administered using a pressurized metered-dose inhaler with a spacer. Candida was detected in 26% of asthmatics treated with fluticasone and in 10% of those treated with beclomethasone (p = 0.02). The inhaled dose of fluticasone was approximately 50% of beclomethasone and both the detection rate and the amount of candida were significantly higher in patients treated with fluticasone. It was concluded that beclomethasone use did not correlate with the amount of candida whereas there was a direct correlation between the amount of candida and the dose of fluticasone. The explanation could be that fluticasone, despite the major anti-inflammatory effects which requires low doses for achieving the therapeutic effect, may impair local immunity due to major solubility, strong inhibition of T cell migration and proliferation, and impaired viability of IL 5 induced eosinophils activation. In addition, the flow rate seems to impact on oral candidiasis susceptibility .These findings were confirmed in a later study that evaluate the use of Fluticasone Propionate (FP) as a dry powder inhaler. In this study, four groups of patients were enrolled: 62 asthmatic patients who were taking 200 μg/day of FP, 122 asthmatics who were taking 500 μg/day of FP, 50 asthmatic patients who had not been on inhaled corticosteroid (ICS) treatment and 40 non-asthmatic subjects. The frequency of positive swabs for Candida colonization was higher in the 500 μg/day FP group than in the asthmatics without ICS (p < 0.05) and it was also higher than normal controls (p < 0.05), whereas there weren’t differences between the 200 μg/day FP group and controls. The most influential variables for Candida colonization in patients who used ICS were the washing of patients’ throats (p < 0.0001) and the duration of ICS treatment more than 12 months (p < 0.05) [In 2007 a study was conducted to evaluate the risk of oropharyngeal and esophageal candidiasis in 40 asthmatic patients above the age of 18 compared to controls. The patients were treated with inhaled steroids (400 mcg to 1600 mcg of budesonide or fluticasone) for at least 1 month. The study distinguished between infection  and colonization (only positive cultures). The results showed oesophageal candidiasis and oropharyngeal candidiasis in 2.5% and 5% of asthmatic patients respectively, while no differences were detected in candida colonizations in the two sites between the asthmatic group and the control group. These findings are not yet conclusive .In order to minimize the incidence of oral candidiasis many preventive measures can be adopted, such as rinsing the mouth and using a spacer device, administering topical antimycotics (e.g. nystatin), using sialogogue medications in patients with low salivary flow rate, and chewing sugar free gums . MoreoveIn summary, the main causes of oral candidiasis could be inhaled steroids (type and dose), This could be prevented by a correct mouth rinsing and using the lowest ICS dose to control the disease.Dental erosion is characterized by the loss of enamel and dentin due to acid action. The pH threshold for dental enamel demineralization is below 5.5 . The preAsthma medications can lead to a higher risk of dental erosion by reducing salivary protection against extrinsic  and intrinsic acids  –8.Furthermore, the main asthmatic drugs, especially the powdered ones, create a pH of less than 5.5, which is the critical level for hydroxyapatite dissolution  Table 22.Table 2Conclusions about the association between dental erosion and asthma have been controversial. A British study conducted in 2000 aimed to assess the level of dental erosion in a random sample of 418 subjects (14 year-olds), 15.8% of them asthmatics. It concluded that the level of dental erosion was higher in asthmatic children than in healthy controls (30% scored 2 vs 24% scored 2 using Tooth Wear Index.) .Another study conducted later in the UK (2003) including more than 1300 (12 years-olds) asthmatic and non-asthmatic children, who were re-examined 2 years later, did not demonstrate a significant difference in erosion prevalence between the two groups. These results can be due to the fact that despite 88% of patients in the asthmatic cohort having drugs prescribed to them, they showed a pH above the critical level of 5.5 . These dThe relationship between gastroesophageal reflux and dental erosion has been proven  and the GOR symptoms are more prevalent in asthmatic patients (approximately 75%) compared to controls  and the A recent cross sectional study (2019) involving 400 children aged 6 to 14 years old, evaluated the relationship between dental erosion and etiological factors. The patients’ risk level of developing dental erosion was obtained from the BEWE index. A statistically significant relationship (p = 0.05) between the intake of carbonated beverages, isotonic drinks and fruit juices and a higher BEWE was detected. Furthermore, regarding the use of drugs that could be potentially erosive, a statistically significant correlation (p = 0.006) was shown with the BEWE index in patients using inhalers  .Interventions such as rinsing the mouth with sodium bicarbonate or using neutral sodium fluoride mouth rinses after using inhalers , using sIn summary, dental erosion may be associated with the use of beta 2 agonists, independently from the type of inhaler, but cofactors like lifestyle, associated drugs, or GERD can increase the risk. Thus, rinsing the mouth and controlling cofactors is mandatory.The periodontium is composed of gingivae, cementum, the alveolar bone, and the periodontal ligament. The initial form of periodontal disease is inflammation of the gingivae (gingivitis) which become swollen, shiny, and easily bleeding. Periodontal health seems to be strongly connected to a proper salivary flow . PeriodoSome studies report a significant amount of accumulated plaque and gingival inflammation in asthmatics . Early iA study was conducted in twenty older asthmatic patients (18–24 years old) with a mean duration of asthma of 13.5 years and twenty matched healthy controls. It demonstrated that the frequency in gingival inflammation was higher (p = 0.01) and the salivary flow was lower (p = 0.01) in the asthmatic group .In addition, a study published in 2017 showed that gingival inflammation  is more prevalent in asthmatic children than in corresponding controls and that it increases with the severity of asthma [A systematic review conducted in 2018, including 21 studies published between 1979 and 2017, showed a strong association between asthma and periodontal disease .Another study published 1 year later, including a systematic review of 11 studies and meta-analysis analyzing six parameters  confirmed a possible association of asthma with periodontal diseases in adults, especially regarding gingivitis . However, the authors outlined that further studies with similar methods are required to evaluate the interaction between these diseases . A crossThe periodontal involvement in asthma could be due to immune and inflammatory processes, to side effects of asthma drugs, or to both . The maiFurthermore, ICS may reduce bone mineral density, including in the mandible . Long teA retrospective study involving a sample of 19,206 asthmatics, found that the hazard of developing periodontal disease increased sharply for patients with a more severe form of asthma . An association between ICS treatment and a higher risk of periodontal disease was detected . HoweverNot only asthma, but also allergic rhinitis and other respiratory diseases promoting mouth breathing could play an important role in developing periodontal affection. For example, obstructive sleep apnea (OSA), adenoid and tonsillar hypertrophy, neuromuscular disorders can affect young children .Dental caries are one of the most common chronic diseases in children and they have been proven to affect systemic health and nutritional status, with a prevalence from 60 to 90% in school children . Its patSeveral studies have demonstrated a strong association between asthma and dental caries, particularly in children, although some other studies were not able to prove this relationship. A possible explanation of the differences between studies could be explained by different fluoride exposures, medication uses, and delivery devices  .Studies also suggest that prevalence of caries increases with the severity of asthma and the duration of treatment . As earlOn the other hand, a systematic review and meta-analysis conducted in 2010 evaluated the effects of asthma on primary dentition (11 articles) and permanent dentition (14 articles) and suggested that asthma doubles risk of caries in both primary and permanent dentition. Although there may be an overestimation of the odds ratio for permanent dentition but not for the primary one found .Another study conducted in an older population (twenty 18–24 years old patients) with a long term duration of asthma (13.5 years), demonstrated a higher incidence of initial caries (6 vs 1.3) and lower salivary secretion rate than in controls without asthma .More recent data come from a study conducted in Korea in 2018. A sample of 44,203 subjects including 1264 patients with asthma, were divided into groups based on the age of diagnosis of asthma (0 to 64 years). Asthma diagnosis in patients younger than 12 years showed a significant correlation with tooth loss due to caries rather than subjects with a delayed diagnosis [Streptococcus mutans. In addition, inhaled beta 2 drugs are connected with a significant decrease in salivary and plaque pH [Ryberg et al. found that the risk of caries in asthmatic children seemed to be associated with the use of beta 2 agonists and consequently lower salivary flow increasing the amount of Lactobacilli and laque pH . Some drlaque pH . Also, aMilano et al. conducted a study in 179 asthmatic children to examine the relationship between the types of drugs, the frequencies of use, and the dosing times of day on dental caries. They noticed that children who used medication more than twice daily experienced more caries in both primary and mixed dentition and also reported a temporal relationship between the medication time and an increase in incidence of caries in primary dentition. This particularly happened in children who had their dosing time before going to bed without cleaning or rinsing their mouth .Two other studies outlined a higher percentage of caries in asthmatics with permanent dentition. In the first, caries were detected in 83% of patients with permanent dentition rather than those with primary (70%) or mixed (78%) ones . The secA cross sectional study conducted in 2016 on over 40 asthmatic patients between the ages of 18 and 65, evaluated the dental status using the DMFT index . Higher values of this score were found in asthmatics in comparison to controls, but the differences were not statistically significant (p = 0.199). For decayed and missing teeth suggesting a higher incidence of caries, the difference between the two groups was statistically different (p < 0.001). Extraction was, in fact, the most common therapy used for caries in the population studied, as the evaluated subjects had been suffering from the disease for about 5 to 10 years and they did not use any preventive dental care (partly due to the lack of information about the drugs’ side effects) .It is important to outline that not only asthma per se and asthma treatment, but also concomitant rhinitis, can influence the incidence of caries. Rhinitis, as documented in ARIA (Allergic Rhinitis and its Impact on Asthma) guidelines, is present in almost 80% of asthmatic patients and could be a confounding factor in the pathogenesis of oral disease in asthmatics, and this has not been investigated in several studies .A retrospective study conducted on 9038 children, observed for 9 years since birth, analyzed the correlation between asthma, rhinitis and caries and the influence of AR drugs in this condition. The authors concluded that there was not any correlation between dental caries and asthma and that the clinical visits for caries were increased by 13–25% in AR patients (p < 0.001). AR medications can also play a role in caries formation by decreasing the salivary flow rate. Second generation antihistamines generally have less anticholinergic effects than first generation ones, but in this study both drugs were used. Furthermore, topical nasal steroids can be connected, not only by reducing salivary flow, but also by changing oral flora. Even if not under specific treatment, AR patients could have increased levels of cariogenic bacteria and mouth breathing, which is a known risk factor for caries formation .In conclusion, in order to reduce the incidence of dental cavities in asthmatics it is suggested to use sugar free medication and fluoridated products to rinse the mouth. Sugary medications and non-regular use of fluoridated rings positively correlate with an increased number of caries. Rinsing and gargling the oral cavity, using spacer devices, and trying to reduce the dosage and frequency of ICS are also recommended .Asthma and even more the therapeutic strategies that are needed in order to achieve the optimal disease control may significantly impact on oral health of affected patients. Patient related risk factors for oral diseases should be carefully assessed and compared with the anti-asthmatic drugs pharmacodynamics and pharmacokinetics characteristics that may amplify the patients’ predisposition. In this way asthma treatment selection and schedule can be tailored in order to minimize the impact of the drug on oral health. Also, when detecting oral diseases in asthmatic patients, a careful revision of both ongoing inhalation drugs and inhalation technique should be performed. Technical errors when assuming the drug may amplify the side effects in the oral districts, by increasing the deposition of drug particles on oral mucosa and dental surface. In fact, patient education plays a central role in maintaining oral health. In particular, oral hygiene, correct dietary habits, and an appropriate use of inhalers are essential.Through a simple evaluation it is possible to optimize the treatment effectiveness and to practice a precision medicine approach for the global well-being of our patients.


Renalase is a flavoprotein that plays a protective role in chronic kidney disease (CKD) and cardiovascular diseases. The secretion and way of action of this protein are still discussed. The aim of our study was to estimate the balance between serum and urine renalase in healthy individuals and CKD patients, using two parameters: fractional excretion (FE) and serum-to-urine renalase ratio (StURR).Our study involved 28 healthy volunteers and 62 patients with CKD in stages I to IV. The concentration of renalase in serum and urine was measured using an enzyme-linked immunosorbent assay (ELISA) kit . We analyzed associations between renalase levels in urine and serum, and other parameters: sex, age, GFR, presence of hypertension, diabetes, and proteinuria, and determined the serum-to-urine renalase ratio and fractional excretion of renalase.p = 0.092). Multivariate analysis performed in the CKD group showed, that from mentioned parameters, serum renalase was the only significant independent factor strongly positively associated with urinary renalase concentration.Renalase and serum-to-urine ratio were significantly higher in CKD patients in comparison with the control group. Fractional excretion was lower in CKD patients but this difference did not reach the statistical significance (The serum-to-urine ratio is significantly and about 6.5-fold higher in CKD patients, and the fractional excretion of renalase is 3-fold, but not significantly lower in CKD patients. Renalase levels in both serum and urine are not related to the glomerular filtration rate and not associated with blood pressure. Renalase is a soluble flavoprotein of the molecular mass of 37.8 KDa, found in blood and urine of humans, rats, and mice –4. Studiconcentration of renalase in blood and urine of healthy subjects and patients with chronic kidney disease, or animal models of CKD, is not extensive and shows some discrepancies. Most of results show, that concentration of renalase in serum of subjects with CKD, hemodialyzed, renal transplant recipients or patients with coronary artery disease (CAD) is higher when compared to healthy subjects  × 1.210 [if black], where SCr (standardized serum creatinine) = mg/dl, age = years. The fractional excretion of renalase (FEp < 0.05), they are shown as median (upper quartile – lower quartile) and compared using the U-Mann Whitney test when comparing two groups or Kruskal-Wallis ANOVA for more than 2 groups. Correlations were measured using the non-parametric Spearman rank correlation test. For qualitative data, Fisher exact test was used. Multivariate analysis was performed using a general linear model (GLM) with concentrations of renalase and its fractional excretion transformed logarithmically to normalize their distributions.Statistical analysis was performed using STATISTICA 12.0 PL software. The distribution of variables was determined using the Shapiro-Wilk W test. Since all quantitative data have distribution significantly different from a normal distribution . Heart rate correlated also negatively with urinary renalase , and positively with urinary creatinine . There was no correlation between FE and any other parameters .In the control group, the diastolic blood pressure (DBP) was significantly higher than in the CKD group. There was no significant difference in systolic blood pressure (SBP). Since elevated arterial pressure was not a criterium for excluding patients from the study, and at the same time appeared to be scientifically significant in terms of renalase concentration, all results were also subjected to statistical analysis. As with patients with CKD, no relationship between renalase concentration and diastolic or systolic pressure was observed. Serum renalase did not correlate with any other parameter. The same observation was made for creatinine. Concerning the urinary renalase/Cr ratio, it correlated moderately negatively with the heart rate .The concentration of renalase in the serum of CKD patients was much higher in comparison to material from healthy individuals. An inverse tendency was observed in urinary renalase values, where excretion of this protein in the CKD group was moderately, but not significantly, lower than in the control group. Urinary renalase/creatinine ratio (ng/mg) did not differ between groups. The FEp > 0.05, Mann-Whitney test) between any of renalase parameters and qualitative parameters of CKD group . Only borderline significant associations of the presence of proteinuria with renalase FE  and StURR  were observed. A comparison of renalase levels between patients in different stages of CKD also shown no significant differences . Median (lower quartile – upper quartile) values of renalase for each stage were: I: 34.73 (20.71–129.7), II: 41 (18.11–104), III: 32.29 (14.15–106.35), IV: 37,67 (26.6–85.77).There were no significant associations (p < 0.001) was observed   as independent variables, showed that serum renalase was the only significant independent factor strongly positively associated with urinary renalase concentration  Table .Table 32 = 0.06, p = 0.72 for the whole model), even for proteinuria , which showed a borderline positive association with renalase FE in univariate analysis.Similar multivariate analysis in CKD group with logarithm of renalase fractional excretion as dependent variable and six covariates listed above as independent variables did not show any significant association  indicating, that they are both removed in a balanced proportion. In renal patients, RNLS probably undergoes a “recycling” mechanism in the kidney or there is a barrier preventing from excess loss of this particular protein, even in patients with proteinuria, as it does not influence urinary renalase concentration.Renalase is a small molecule that should be easily filtered by the kidney, however, there is still no consensus regarding the mechanism on which renalase regulation and action is based. As with many other factors, its accumulation may be caused by abnormal production and secretion of this protein, together with limited filtration capacity or impaired filtration due to structural or functional abnormalities of the kidney. Due to the potentially protective effect of renalase, this filtration may be also limited physiologically, or renalase could be reabsorbed under conditions of increased demand for this protein. As already shown in many studies, the elevation of renalase is observed e.g. after acute exercise, when its expression in skeletal muscles increases, and decreases in other tissues indicating that it is a reaction to oxidative stress . A simil tissues . This re tissues . As our The elevation in serum renalase has been also repeatedly associated with heart and circulatory dysfunctions, very common in the CKD, since heart seems to be another very important source of RNLS. Low concentration of renalase is considered as one of the predictive factors of coronary artery disease (CAD) , 12, 22,The urinary renalase/Cr (ng/mg) ratio was firstly described in 2014 and only for healthy children and adolescents . The autWe have evaluated the serum-to-urine ratio, which is significantly and about 6.5-fold higher in CKD patients, and the fractional excretion of renalase, which is 3-fold, but not significantly lower in CKD group. Therefore, there must be a mechanism that prevents renalase from escaping through the glomerular filtration barrier in renal patients. Renalase concentration is also unrelated to the glomerular filtration rate and is not associated with blood pressure both in healthy people and CKD patients. Similar research should be performed in cardiac patients without kidney diseases to re-discuss the role of renalase in cardiovascular diseases.We are aware that our study has some limitations, mainly related to a relatively small group of respondents. Also, the control group consisted of people from the same small environment, and the volunteers from the control group were significantly younger than patients with CKD. At the same time, age does not correlate either with the concentration of renalase or with eGFR, so this fact should not have an important impact on results. The rather limited discussion results from the absence of similar studies and further considerations would be purely speculative.


Cognitive impairment (CI) is not uncommon in dialysis patients. Various factors have been implicated. This study aims to examine mutual interaction of various clinical factors for CI in patients receiving hemodialysis. A total of 48 hemodialysis patients in outpatient clinic were recruited from 2015 to 2017. Demographics, circulating uremic toxin concentrations, miRNA concentrations, and nerve injury protein concentrations were collected. Clinical dementia rating (CDR) scores were used to stratify the functional scores of the patients. Receiver operating characteristic (ROC) analysis was used to evaluate diagnostic test performance for predicting dichotomous results, and cumulative ROC analysis was used to examine the combined contribution of clinical factors. CDR scale 0 included 15 patients ; CDR > 0.5 included 33 patients . On cumulative ROC analysis, the major predictors of mild CI were hemoglobin, age, sex, homocysteine, neuron-specific enolase (NSE), and miR-486. The cumulative area under the curve (AUC) on combining hemoglobin, age, and miR-486 was the highest . Two dichotomized variables reached 81.82% sensitivity and 86.67% specificity, with the likelihood ratio for positive and negative results being 6.14 and 0.21, respectively. In conclusion, hemoglobin, age, and miR-486 display high-degree combined effects on mild CI in patients receiving hemodialysis. Cognitive impairment (CI) has a high prevalence in chronic kidney disease (CKD), especially in elderly patients ,2,3. TheThe CI observed in CKD influences not only daily life and ability to work but also results in longer hospitalization and higher risk for mortality ,16,17. IAlthough various factors may contribute to CI in patients with CKD, these factors are generally treated individually, without considering possible mutual interactions. Recently, receiver operating characteristic (ROC) analysis is being widely used to evaluate diagnostic test performance for predicting dichotomous results by comparing sensitivity and specificity ,19. FurtIn the current study, we aimed to use ROC analysis to examine the contribution between demographics (age and sex), routine biochemistry variables, uremic toxins, and miRNAs for CI prediction in patients receiving hemodialysis. We also aimed to identify high risk factors through cumulative ROC analysis.2 and bicarbonate-based dialysate. A total of 114 potentially eligible hemodialysis patients were screened. Finally, a total of 48 patients receiving hemodialysis were enrolled for analysis  age ≥ 18 years; (2) subjective memory complaints; and (3) ability to provide basic interview, meaning no aphasia. The exclusion criteria included (1) history of cerebral stroke or brain injury by nonmedical causes; (2) drug-usage history, which may influence cognitive function, including chemotherapy; (3) other comorbidities, which may affect cerebral function, e.g., liver cirrhosis, cancer, and psychiatric diseases; (4) malnutrition, serum albumin level <3.5 g/dL; (5) alcoholism; (6) pregnancy; (7) hospitalization within 3 months of enrollment; and (8) absence of caregiver for providing medical history. All of the participants underwent hemodialysis thrice weekly with dialyzers of surface area ≥2.0 manalysis . The stuBlood sampling was performed mid-week (Wednesday/Thursday) with fasting status for participants who had received hemodialysis. Blood test was conducted for hemoglobin (Hb) and uremic toxins. Uremic toxins included (1) small water-soluble solutes, such as blood urea nitrogen (BUN), creatinine (Cr), calcium (Ca), phosphorus (P), asymmetric dimethylarginine (ADMA), and 8-hydroxy-2-deoxyguanosine (8-OHdG); (2) protein-bound solutes, such as p-cresyl sulfate (PCS), indoxyl sulfate (IS), and homocysteine; and (3) medium-sized molecules: interleukin 1-β (IL-1β), interleukin 6 (IL-6), interleukin 18 (IL-18), tumor necrosis factor-α (TNF-α), intact parathyroid hormone (iPTH), and β2 microglobulin. Blood samples for BUN, Cr, Ca, P, and glutamate oxaloacetate transaminase (GOT) were analyzed using commercial kits and an autoanalyzer . The PCS and IS were quantified using HPLC .iPTH was measured by chemiluminescent immunoassay . Measurements of ADMA, 8-OHdG, IL-1β, IL-6, IL-18, and TNF-α were performed using ELISA. β2 microglobulin level was measured using a turbidimetry method .We measured 3 nerve-injury-related proteins in the blood using ELISA: neuron-specific enolase (NSE); heat shock protein (HSP) 70, and S100B.We selected candidate miRNAs from peripheral mononuclear cells using next-generation sequencing (NGS). The candidate miRNAs were selected if their blood levels were higher than 1.5-fold in patients receiving hemodialysis compared to healthy volunteers. Thus, 4 miRNAs were identified: miR-134, miR-182, miR-451, and miR-486.The collected RNA samples were first subject to quality examination with Bioanalyzer 2100 (Agilent) facility. The RNA samples with RIN  value ≥ 8.0 were prepared with TruSeq small RNA preparation protocol , followed by sequencing with a V3 150-cycle sequencing reagent on the MiSeq facility (Illumina) to generate 51-nt single-end reads. The generated NGS data were analyzed with miRSeq tool kit file:///D:/Documents/My_Papers/FINISHED/51_ADHD_miRNA_Diagnosis panel/SUBMISSION/Manuscript_R1.doc - _ENREF_1#_ENREF_1  with def−ΔCt), where ΔCt = Ct target − U6.For quantitative PCR of the miRNAs, 10 ng of total RNA was converted into cDNA using the TaqMan MicroRNA Reverse Transcription kit . The expression of mature miR-134, miR-182, miR-451, miR-486, and U6  was quantified using the commercially available TaqMan Universal Master Mix No Amp UNG  in a 7500 Real-Time PCR System. The qRT-PCR was performed at 95 °C for 10 min, followed by 40 cycles of 95 °C for 15 s and 60 °C for 1 min. Expression levels of the miRNAs were normalized to that of the internal control, U6, using the equation log ; this test have been validated in the Chinese population ,22. We ut-test or χ2 test, as appropriate. In addition, the effect size of continuous variables between groups was estimated using Cohen’s d from the t-test. The dichotomous result of each variable was determined by individual ROC analysis. Higher individual area under the curve (AUC) represented better prediction performance for high CDR scores. The variables were then ranked by individual AUCs estimated from individual ROC analysis.The distribution of variables between the groups was summarized in terms of mean (standard deviation), median (interquartile range), or frequency (percentage). The difference between the groups was estimated using the independent two-sample A cumulative ROC analysis was performed to detect the combined effects of the measurements used to predict a high CDR score. Positive changes in the cumulative AUCs were tracked along with the cumulated variables until the addition of other variables no longer increased the cumulative AUC. In cumulated ROC analysis, the likelihood ratio was used to assess high CDR scores in subjects with different cumulative scores. The LR+ (sensitivity/[1 − specificity]) represented the ratio of the probability of a positive test for subjects with high CDR scores to that of a positive test for subjects with low CDR scores. Therefore, the LR− ([1 − sensitivity]/specificity) represented the ratio of the probability of a negative test for subjects with high CDR scores to that of a negative test for subjects with low CDR scores. The 95% confidence interval (CI) for sensitivity, specificity, and likelihood ratios were computed.p-value of less than 0.05 was considered statistically significant. All statistical analyses were performed using STATA version 11.0.Variables that contributed to positive changes for the highest cumulative AUC were selected for further analysis. The cumulative risk score for each subject was obtained by adding the risk score (1 or 0) of selected variables that contributed to the high CDR score. For each subject, the cumulative risk score represented the total number of risk factors. For instance, a score of 5 was interpreted as the presence of 5 risk factors that were most relevant to a high CDR score. In general, a limited sample size provides unusable results  and also generates an overfit model in regression analysis. Considering the abovementioned limitations, we conducted logistic regression and only included the most contribute factors for mild cognitive impairment in patients receiving hemodialysis derived from cumulative ROC results. A t-test, p = 0.009; Cohen’s d 0.88) and the Hb level was higher in patients with CDR ≥ 0.5 . The candidate miRNA analysis did not show significant difference in the blood levels of miR-134, miR-182, miR-451, and miR-486 ; CDR ≥ 0.5 included 33 patients . There were no significant differences in the blood levels of biochemical variables, small water-soluble solutes, protein-bound solutes, medium-sized molecules, and molecular markers of nerve injury, except that the BUN level was higher in patients with CDR 0  = 2.74 (1.13–6.67), p = 0.026) and miR-486 (univariate: 4.24 (1.14–15.79), p = 0.031; multivariate: OR (95% CI) = 7.54 (1.47–38.6), p = 0.015) were significantly associated with mild cognitive impairment. Afterward, the 2-order interaction analysis, including Hb*Age OR (95% CI) = 1.01 (1.001–1.01), p = 0.019), Hb*miR-486 (OR (95% CI) = 1.17 (1.0–1.32), p = 0.016) and age*miR-486 (OR (95% CI) = 1.03 (1.004–1.05), p = 0.019) were given. The results indicated that all three combinations in 2-order interaction level were significantly associated with mild cognitive impairment in hemodialysis patients. Unfortunately, the 3-order interaction analysis were omitted due to the limited sample size and current regression algorithm. Overall, the 2-order interaction results were consistent with the cumulative ROC findings, which indicated that hemoglobin, age, and miR-486 were associated with mild cognitive impairment in patients receiving hemodialysis under certain interaction effects.The cumulative ROC results indicated that Hb, age, and miR-486 exerted major contribution; hence, we included these variables for logistic regression analysis . The uniOne of the risk factors for CI is CKD. The potential causes involve vascular and neurodegenerative mechanisms . The impIt has been reported that Hb shows a U-shaped association with cross-sectional cognitive function ,26. The Aging is a natural process in organisms. Complex sophisticated coordinated mechanisms among tissues and organs are involved in the aging process. Commonly, aging is characterized by the progressive decline in functions of tissues and organs. Eventually, aging contributes to the risk of disease occurrence. In the past decades, studies have investigated the molecular mechanisms of aging in different tissues ,30,31,32Sex showed the fourth-highest AUC in our study. The cumulative AUC of Hb, age, sex, and miRNA-486 was 0.874. This finding indicates that sex plays an important role in CI of patients in Taiwan receiving dialysis. A nationwide survey in Taiwan showed that women had a higher prevalence than men for overall dementia and mild CI . The exaWe analyzed the contribution of several uremic toxins to CI in our study. Among them, homocysteine showed the highest AUC in individual ROC analysis. Homocysteine is a protein-bound solute and is commonly elevated in patients with CKD. On conversion to homocysteic acid, homocysteine can activate N-methyl-D-aspartate receptor, thus leading to a direct neurotoxic effect . HomocysGABRB3, encodes gamma-aminobutyric acid receptor subunit beta-3 (GABRB3), which is a member of the ligand-gated ion channel family [Circulating miRNAs have been reported to be biomarkers of mild CI. Two sets of miRNA pairs—miR-132 and miR-134 families—were shown to differentiate patients with mild CI from age-matched controls . Next-gel family . Gamma-al family . Howeverl family  in patiel family . One conl family . BecauseA total of 152 uremic toxins have been detected, and these molecules have been shown to exert various negative effects, such as anorexia, cardiac failure, anemia, immune dysfunction, malnutrition, inflammation, and skin atrophy ,42. UremIn our study, we measured blood levels of nerve-injury-related proteins, such as NSE, HSP 70, and S100B; NSE was one of the top-ranked variables on cumulative ROC analyses. It is a glycolytic isoenzyme expressed in the central and peripheral neurons and neuroendocrine cells. In rats, NSE immunofluorescence signal decreased in the affected neurons 2–10 days following axonal injury. There is accumulating evidence that the level of NSE in neurons serves as a marker of axon injury, regeneration, and target reinnervation ,47,48. AThe present study is subject to several limitations. Firstly, our study did not include a follow-up interval, and the cumulative ROC approach was limited to cross-sectional clinical data. This may ignore all possible combinations of complex interactions when the effect of time is considered. Secondly, our study did not include other possible factors affecting CI in patients receiving dialysis, such as economic and social status and comorbidities. Thirdly, we did our best to examine the implicated uremic toxin levels in our patients. However, there are several uremic toxins that we did not examine. Therefore, their contribution to CI in these patients was not investigated. Fourthly, the sample size was relatively small, and all the participants were Taiwanese. The possible effect of ethnicity cannot be ruled out in our study. Despite the above limitations, the strength of our study is in being the first investigation on a combination of specific clinical factors predicting mild CI in hemodialysis patients. This approach not only provides an alternative insight into the plausible mechanisms for CI but also a method for CI prediction in such patients.The cumulative ROC analysis provides better AUC performance than individual ROC analysis for identifying factors for prediction of mild CI in patients receiving hemodialysis. Our proposed scoring system identified six clinical factors that displayed a high degree of combined effect for mild CI in patients receiving hemodialysis.


Introduction: The dipping phenomenon is a physiological drop in blood pressure (around 10–20%) during sleep and represents an event related to the circadian blood pressure trend. This phenomenon, in some cases, is characterized by some alterations that can be expressed by an increase (extreme dipping), a decrease (non-dipping), or a reverse  physiological decline of blood pressure. Few studies focused on the association between the circadian variation of blood pressure and psychological variables, although this information could help understanding how psychological characteristics  interact with individuals’ physiological processes. Given the association between emotional dysregulation and essential hypertension, this study aimed to investigate the relationship between alexithymia and dipping status in a sample of healthy and hypertensive adults in the absence of other medical conditions. Methods: Two hundred and ten adults took part in the study and were classified, according to ambulatorial blood pressure measure (ABPM), into three groups: dippers (n = 70), non-dippers (n = 70), and extreme dippers (n = 70). The participants completed a socio-demographic and anamnestic interview and the Toronto Alexithymia Scale-20 (TAS-20). Results: The ANOVAs on the TAS-20 subscales showed that the groups differed in the difficulty identifying feelings and difficulty describing feelings. In both the subscales, dippers showed lower scores than non-dippers and extreme dippers. The ANOVA on the global score of TAS-20 confirmed that dippers were less alexithymic than both extreme dippers and non-dippers. Conclusions: This study confirms that some psychological factors, like alexithymia, could represent a characteristic of patients who fail to exhibit an adaptive dipping phenomenon. Moreover, an association between an excessive reduction of BP (extreme dipping) or a lack of the decrease of BP during sleep (non-dipping) and a worse emotional regulation, considering alexithymia construct, was highlighted for the first time, confirming the relevant role of the emotional process in the modulation of an essential psychophysiological process such as the circadian variation of BP. The circadian variation of sympathetic activity during night-time is physiologically accompanied by an increased vagal tone and a marked reduction in heart rate, cardiac output, and total peripheral resistance. As a consequence of these autonomic variations, blood pressure (BP) drops during the bed-rest period. Typically, the physiological night-time drop or “dip” of BP ranges between 10 and 20% compared with daytime BP . HoweverAccording to recent hypertension guidelines, assessment of nocturnal BP values and dipping status is enabled by 24-h ambulatory blood pressure monitoring (ABPM), which allows the classification of patients in four different circadian BP phenotypes: (a) dipping: physiological decrease of 10–20%; (b) non-dipping: reduction of night-time BP less than 10%; (c) reverse dipping: a rise of night-time BP; and (d) extreme dipping: a night-time BP decrease higher than 20% [The physiological dipping pattern appears to be a protective factor for cardiovascular health . ConversIt is well known that many psychological factors play an important role in the development and maintenance of altered BP and essential hypertension. The studies focused on hypertension have found an association of hostility, depression, anxiety, coping strategies, and emotional dysregulation with alteration of the normal level of blood pressure ,12,13,14For the first time, the current study investigates the association between alexithymia, an emotional dysregulation construct, and the BP dipping status. Previous evidence reported higher emotional dysregulation in people with essential hypertension ,13. Moren = 70) who had a dipping ratio between 0.80 and 0.90; non-dippers (n = 70) who presented a dipping ratio higher than 0.90; and extreme dippers (n = 70) who showed a dipping ratio lower than 0.80.Two hundred and ten participants were recruited at the First Medical Clinic of the Policlinico Umberto I of the University of Rome “Sapienza”. A cardiologist provided information about the hypertensive status and dipping conditions. The participants were divided into three groups, according to their bed-time drops of BP: dippers (The inclusion criteria for the study were: (a) age between 40 and 75 years and (b) dipping classification performed by a cardiologist after a 24-h ABPM. The exclusion criteria were a diagnosis of chronic or severe medical and psychiatric pathologies .The main characteristics of the samples are shown in Blood pressure office evaluation: systolic (SBP) and diastolic Blood Pressure (DBP) and heart rate were recorded by using an automatic electronic sphygmomanometer  validated for self-measurement . Blood pressure measurement was performed according to the European guidelines for hypertension .2), an indirect estimate of the individual’s body fatness.Weight status assessment: weight and height, assessed by a balance and a stadiometer, were used to calculate the body mass index . The ABPM was set to obtain BP recordings at 15 min intervals during the wake (time range of daily blood pressure: 07:00 to 22:00) and 30 min intervals during sleep (time range of night blood pressure: 22:00 to 07:00) . AccordiFurthermore, they recorded whether they were out of bed during the night  and the relative awake time. This strategy allows excluding the “out-of-bed” records of the ABPM from the data. Another exclusion criterion for the measurements was the presence of SBP data greater than 240 mmHg or lower than 70 mmHg or DBP data higher than 150 mmHg or lower than 40 mmHg. The ABPM dataset included in the analysis should have at least two-thirds of the SBP and DBP measurements during both the daytime and the night-time periods . HoweverDemographic data , lifestyles , medical, and psychiatric information were collected for each patient by face-to-face interviews.TAS-20 ,28: a 20The study was conducted according to the Declaration of Helsinki and was approved by the Local Ethics Committee . After the informed consent was signed, each participant was subjected to office blood pressure assessment; then, weight and height were recorded. Finally, the participants completed the socio-demographic and anamnestic interview and the TAS-20 questionnaire. After this procedure, a cardiologist gave the eventual diagnosis of essential hypertension and classified the dipping status according to the ABPM registration.One-way analyses of variance (ANOVAs) were carried out considering the group as the independent variable  and the different socio-demographic , physiological , and lifestyle  dimensions as dependent variables.Finally, ANOVAs on the TAS-20 subscales and TAS-20 global scores were conducted. Planned comparisons were used to analyze significant effects.2) was adopted to estimate the differences in the percentage of normotensive, untreated hypertensive, and treated hypertensive participants in the three groups. For all the statistical analyses, the level of significance was accepted at p ≤ 0.05. Statistical analyses were performed through the Statistica Software v.10.0 .The Chi-squared test ; non-dippers were older than both dippers  and extreme dippers . No differences were highlighted between dippers and extreme dippers . Considering years of education , BMI , systolic blood pressure , diastolic blood pressure , cigarette consumption , and alcohol consumption , no significant differences were observed among the groups (see The ANOVA on age showed significant differences between groups (Foups see .The ANOVAs on the two indices of MAP (day and night) showed significant differences.2,207 = 4.24; p = 0.02; pƞ2 = 0.04) extreme dippers showed higher values than dippers  and non-dippers , while dippers and non-dippers were not different . Considering MAP of night time , extreme dippers showed lower values than both dippers  and non-dippers ; and dippers showed lower values than non-dippers  (Considering MAP of day time (F 0.0001) .2,207 = 5.63; p = 0.005; pƞ2 = 0.05) and the difficulty describing feelings . Dippers showed lower scores in both the TAS-20 subscales than non-dippers .Externally oriented thinking did not result different among the three groups ; dippers showed lower levels of alexithymia than both non-dippers  and extreme dippers , while there were no differences between non-dippers and extreme dippers   see .Since age was significantly different between groups, it was introduced as covariates in the analyses; however, no substantial differences were found. ANOVAs confirmed all significant differences.2,171 = 6.28; p= 0.002; pƞ2 = 0.06), difficulty describing feelings , externally oriented thinking  and global score . Planned comparison confirmed that extreme dippers and non-dippers reported higher TAS-20 scores compared to dippers in difficulty identifying feelings , difficulty describing feeling  and the global score ,In the hypertensive patients, the ANOVAs showed significant differences in the difficulty identifying feelings (Fp > 0.05).No differences were reported in normotensive participants  plays a crucial role in this relationship because it appears to be the main mediator of the circadian variation in blood pressure, and it is related to emotional response . In partAlexithymia is characterized by somatosensory amplification and hyperarousal, and these features disturb the affective arousal induced by external stimuli . The altThe results concerning externally oriented thinking are in line with this assumption. In our sample, no differences between groups were found in this alexithymic dimension. This result could occur because externally oriented thinking refers more to a cognitive level of emotional process, whereas difficult to identify and describe feelings are closely related and refer to the subjective experience of emotions that are strictly associated with the hyperactivation of the sympathetic nervous system and the consequent hyperarousal ,42.When the relationship between the dipping status and alexithymia was separately examined in hypertensive and normotensive participants, a higher emotional dysregulation in extreme dipper and non-dipper individuals was confirmed only in hypertensive patients. This finding suggests that alexithymia may be associated with an alteration of the cardiovascular system in hypertensive participants, which would further compromise hypertension. Moreover, this result could indicate that the well-known relationship between hypertension and alexithymia, e.g., ,13,14, iThe findings of this study are interesting because they were highlighted also controlling a possible influence of demographic (such as gender and years of education), physiological (BMI), and lifestyle  factors that did not differ among the groups. Only the age was different in the three groups, but the observed results were maintained by introducing this variable as a covariate in the analyses. Moreover, dippers were not different from non-dippers and extreme dippers in the prevalence of normotensive, hypertensive untreated, and hypertensive treated participants. A previous study  reportedGenerally, the importance of controlling the role of the psychological aspects in the circadian variation of BP and the dipping phenomenon was reinforced by the present findings. Moreover, contrary to previous studies that considered dipping status as a dichotomic or continuous phenomenon, our results underlined the importance of a multi-dimensional classification, which considers the different forms of nocturnal blood pressure variation .Although the results are promising, the current study presents some limitations, such as the small sample size. This factor underlines the need to replicate these findings in larger community samples to generalize these results to the general population. Another limit was represented by the use of the ABPM for the assessment of BP. ABPM is characterized by a poor reproducibility of measurements, as highlighted by some authors . HoweverThe absence of drug treatment analysis represents another limit because we do not know how antihypertensive treatment could have affected the BP circadian variations. It would be useful to analyze this aspect, which can mediate the relationship between psychological and physiological aspects ,17. The Although the knowledge on the association between blood pressure and psychological factors has increased in the last years, confirming the role of different psychological aspect in different types of hypertension ,12,17, lIt would be useful to fully understand how blood pressure interacts with other individual traits, such as psychological dimensions, to improve the diagnosis and treatment of hypertension and related disorders.Our findings suggest that psychological factors may contribute to the description and classification of patients who fail to exhibit adaptive nocturnal blood pressure dipping. It is interesting to note that the relationship between emotional dysregulation, i.e., difficulty identifying and describing feelings, and excessive BP reduction during sleep (extreme dipping) underlines that some psychological aspects could affect the absence of dipping and a maladaptive increase of the dipping phenomenon. These findings suggest that alterations in the circadian pattern of BP can be linked to emotional dysregulation in a non-linear way that should be further examined.