Microalbuminuria and its Prognostic Significance in Patients with Acute Heart Failure with Preserved, Mid-Range, and Reduced Ejection Fraction. / Microalbuminúria e seu Significado Prognóstico em Pacientes com Insuficiência Cardíaca Aguda com Fração de Ejeção Preservada, Intermediária e Reduzida.

BACKGROUND: The prevalence and significance of microalbuminuria have not been well studied in patients with different heart failure subtypes. OBJECTIVE: The prevalence and significance of microalbuminuria have not been well studied in patients with different heart failure subtypes. Therefore, we aimed to investigate the frequency and prognostic value of microalbuminuria in patients hospitalized for acute heart failure (AHF) with preserved ejection fraction (HFpEF), mid-range ejection fraction (HFmrEF), and reduced ejection fraction (HFrEF). METHODS: All consecutive adult patients referred to the hospital due to AHF between June 2016 and June 2019 were enrolled. Microalbuminuria is defined as urinary albumin to creatinine ratio (UACR) level in the range of 30-300 mg/g. Hospital mortality was the endpoint of this study. RESULTS: Of the 426 AHF patients (mean age 70.64 ± 10.03 years, 53.3 % female), 50% had HFrEF, 38.3% had HFpEF, and 11.7% had HFmrEF at presentation.The prevalence of microalbuminuria was 35.2%, 28.8%, and 28.0% in HFrEF, HFpEF, and HFmrEF, respectively. A total of 19 (4.5%) patients died during the in-hospital course, and in-hospital mortality was higher in HFrEF patients (6.6%) compared to patients with HFpEF (2.5%) and HFmrEF (2.0%). Multivariate analysis showed that the presence of microalbuminuria predicted in-hospital mortality in patients with HFrEF and HFmrEF but not in HFpEF. CONCLUSION: Although microalbuminuria was common in all subgroups of AHF patients, it has been found to predict prognosis only in patients with HFrEF and HFmrEF.

FUNDAMENTO: A prevalência e o significado da microalbuminúria não foram bem estudados em pacientes com diferentes subtipos de insuficiência cardíaca. OBJETIVO: A prevalência e o significado da microalbuminúria não foram bem estudados em pacientes com diferentes subtipos de insuficiência cardíaca. Portanto, nosso objetivo foi investigar a frequência e o valor prognóstico da microalbuminúria em pacientes hospitalizados por insuficiência cardíaca aguda (ICA) com fração de ejeção preservada (ICFEp), fração de ejeção de faixa média (ICFEfm) e fração de ejeção reduzida (ICFEr). MÉTODOS: Todos os pacientes adultos consecutivos encaminhados ao hospital devido a ICA entre junho de 2016 e junho de 2019 foram inscritos. A microalbuminúria é definida como o nível de albumina urinária para relação de creatinina (AURC) na faixa de 30­300 mg/g. A mortalidade hospitalar foi o critério de valoração deste estudo. RESULTADOS: Dos 426 pacientes com ICA (idade média de 70,64 ± 10,03 anos, 53,3% do sexo feminino), 50% tinham ICFEr, 38,3% tinham ICFEp e 11,7% tinham ICFEfm na apresentação. A prevalência de microalbuminúria foi de 35,2%, 28,8% e 28,0% em ICFEr, ICFEp e ICFEfm, respectivamente. Um total de 19 (4,5%) pacientes morreram durante o curso intra-hospitalar, e a mortalidade intra-hospitalar foi maior em pacientes com ICFEr (6,6%) em comparação com pacientes com ICFEr (2,5%) e ICFEfm (2,0%). A análise multivariada mostrou que a presença de microalbuminúria previu mortalidade intra-hospitalar em pacientes com ICFEr e ICFEfm, mas não em ICFEp. CONCLUSÃO: Embora a microalbuminúria fosse comum em todos os subgrupos de pacientes com ICA, descobriu-se que ela prediz o prognóstico apenas em pacientes com ICFEr e ICFEfm.

In-hospital mortality of acute pulmonary embolism: Predictive value of shock index, modified shock index, and age shock index scores.

OBJECTIVE: The shock index (SI), modified shock index (MSI), and age shock index (ASI) have been reported to predict adverse outcomes in patients with different acute cardiovascular conditions. This study aimed to investigate the association between these indexes and in-hospital mortality in patients with acute pulmonary embolism. METHODS: The medical records of all adult patients who were hospitalized with acute pulmonary embolism between June 2014 and June 2019, were examined. Collected data included vital signs, demographic characteristics, comorbidities, and laboratory values on presentation. The predictive value of SI, MSI, ASI, and pulmonary embolism severity index (PESI) for predicting in-hospital mortality were compared by C-statistics. RESULTS: A total of 602 consecutive patients (mean age 66.7±13.2 years, 55% female) were included, and 62 (10.3%) of the patients died during their in-hospital course. The admission SI, MSI, ASI, and PESI were significantly higher in the deceased patients. After adjusting for other factors, the SI, MSI, PESI, and ASI were independent predictors of in-hospital mortality. The prognostic performance of ASI (C-statistics 0.74) was better than MSI (C-statistics 0.71), SI (C-statistics 0.68), and PESI (C-statistics 0.65). CONCLUSION: The ASI may be used to identify patients at risk for in-hospital mortality following acute pulmonary embolism.

External validation of the ACUTE HF score in patients hospitalized for acute decompensated heart failure.

OBJECTIVE: Recently, the ACUTE HF score has been developed as a new tool for predicting short and long term mortality in patients with acute heart failure (AHF). However, this. score has not yet been validated externally. The present study aimed to investigate the prognostic value of ACUTE HF score in a different patient cohort. METHODS: We retrospectively enrolled all consecutive adult patients hospitalized due to AHF between January 2016 and January 2019. The ACUTE HF score is calculated by 7 different variables including age, creatinine, non-invasive ventilation, history of stroke or transient ischemic attack, left ventricular systolic function, mitral regurgitation and history of hospitalization.The primary endpoint of the study was in-hospital mortality. RESULTS: A total of 418 AHF patients (mean age 70.2 ±â€¯11.3 years, 52% male) were included, and 26 (6.2%) patients died during the in-hospital course. Patients in the study were divided into three groups according to ACUTE HF score: low-risk (<1.5, n = 210), intermediate-risk (1.5-3, n = 50), and high-risk groups (>3, n = 158). The multivariate analysis showed that the ACUTE HF score was an independent predictor of in-hospital mortality(OR: 2.15; 95% CI, 0.94-4.34; p < 0.001). CONCLUSION: The ACUTE HF score was a useful prognostic score for the prediction of in-hospital mortality in patients with AHF. Further validation studies in different regions of the world and with different AHF populations are needed to determine its generalisability.

Evaluation of the Nexus X-ray rules in blunt thorax trauma.

BACKGROUND: There is still no agreed radiographic rule for the evaluation of blunt thoracic trauma. Emergency physicians want radiography according to their experience and examination findings. Various studies have been carried out on this subject and some of these studies have reached findings that can support the initial steps of the rules of radiography. One of them is the rule of Nexus thorax radiography rules. In this study, we aim to determine the accuracy of nexus thorax radiography rules. METHODS: Our study was a prospective cohort study performed in the emergency department of our University Hospital. In this study, 690 patients were evaluated. RESULTS: As a result of our study, we observed that patients were asked for more thoracic trauma because of chest pain, palpation tenderness in the thorax and sudden deceleration mechanism and pathology was found in approximately 25% of all imaging. The most common pathology we observed was rib fracture. Approximately 45% of the patients underwent thorax CT, and thorax CT was the most frequently requested for the detailed examination. When we evaluate the patients according to nexus thorax radiography rules, it was seen that the mechanism of sudden deceleration, intoxication and the disturbing, painful injury was more important than other parameters. The overall sensitivity and specificity of Nexus thorax radiographs were found to be 98% and 38%, respectively. CONCLUSION: In the evaluation of blunt thoracic trauma, the rules of nexus thorax radiography are considered useful concerning pathological detection.

Prognostic value of microalbuminuria on admission in patients with acute pulmonary embolism.

OBJECTIVE: There have been no studies examining the effect of microalbuminuria on outcomes of patients with acute pulmonary embolism (APE). This study aimed to assess the association between microalbuminuria and in-hospital mortality in patients with APE. METHODS: This retrospective study included all adult patients hospitalized due to APE between June 2015 and May 2018. Blood and urine samples were collected before the diagnostic procedures on admission. Patients were divided into 3 groups according to urinary albumin to creatinine ratio (UACR) levels: normoalbuminuria (<30 mg/g), microalbuminuria (30-299 mg/g), and macroalbuminuria (> 300 mg/g). The primary endpoint of the study was in-hospital mortality. RESULTS: A total of 154 consecutive patients (mean age 69.8 ± 13.4 years, 51.9% female) were included, and 21 (13.6%) of the patients died during their in-hospital course. The prevalence of normoalbuminuria, microalbuminuria, macroalbuminuria was 70.1%, 23.4%, and 6.5%, respectively. Patients with in-hospital mortality had significantly lower estimated glomerular filtration rate (eGFR), but higher UACR at admission than those patients who survived. As compared with patients with normoalbuminuria, multivariate analyses showed that the patients with microalbuminuria and macroalbuminuria had 2.38-, and 3.48-fold higher risk for in-hospital mortality, respectively (p < 0.001). Multivariate analyses also showed that UACR >102.6 mg/g (OR: 1.76; 95% CI, 0.99-3.16; p = 0.011) was independently associated with in-hospital mortality, while a low eGFR was not associated. CONCLUSION: Microalbuminuria at admission may allow rapid prediction of prognosis in patients with APE.

Comparison of objective nutritional indexes for the prediction of in-hospital mortality among elderly patients with acute heart failure.

OBJECTIVES: The association between objective nutritional indexes and prognosis in patients with acute heart failure have not been well studied. Therefore, we aimed to compare the prognostic value of modified Glasgow prognostic score, prognostic nutritional index, controlling nutritional status score, and geriatric nutritional risk index for the prediction of in-hospital mortality in patients with acute heart failure. METHODS: All consecutive elderly patients (aged ≥65 years) who had tests for C-reactive protein, total lymphocyte count, total cholesterol, and albumin levels at admission, and hospitalized due to acute heart failure were retrospectively included. The primary endpoint of the study was in-hospital mortality. We used a base model for the prediction of in-hospital mortality, including age, gender, log N-terminal pro-B-type natriuretic peptide, and the presence of coronary artery disease. We added each of the malnutrition scores, in turn, to the base model and used C-statistics to evaluate model discrimination in survival analysis. RESULTS: A total of 628 patients were included, and 80 (12.7%) of the patients died during the hospital stay. Multivariate analysis showed that older age, prognostic nutritional index < 41.2, controlling nutritional status score > 5, geriatric nutritional risk index <92, and modified Glasgow prognostic score were independent predictors of in-hospital mortality. Among the malnutrition scores, geriatric nutritional risk index increased model performance most compared with base model. CONCLUSION: Though all objective nutritional indexes were associated with prognosis in elderly patients with acute heart failure, geriatric nutritional risk index was superior to other scores in predicting in-hospital mortality.

Epicardial fat thickness is increased and associated with disease severity in hidradenitis suppurativa.

Previous studies showed an association between various dermatological diseases and epicardial fat thickness (EFT). However, EFT, which has been accepted as a cardiometabolic risk factor in recent years, has not been studied in the context of hidradenitis suppurativa (HS). Therefore, we aimed to determine whether EFT is increased in HS patients, and whether EFT is associated with disease severity. Forty adult patients with HS and 100 age- and sex-matched controls were included. Patients with diabetes mellitus, cardiovascular diseases, chronic renal or hepatic diseases, or other inflammatory conditions were excluded. The EFT was measured by transthoracic echocardiography. Disease severity was assessed by Hurley stage, and stage III patients have been described as having severe disease. High-sensitivity C-reactive protein (hs-CRP) and EFT were significantly higher in HS patients compared to controls. There were positive correlations between EFT and the duration of the disease, hs-CRP, and Hurley stage. The EFT was proportionally increased in HS patients with increasing disease severity; the largest EFT was found in Hurley stage 3 patients (7.34 ± 2.30 mm), followed by Hurley stage 2 patients (6.12 ± 1.82 mm), and Hurley stage 1 patients (4.83 ± 0.98 mm). Multivariate analysis showed that male gender, hs-CRP, body mass index, and EFT ≥ 5.9 mm were independent predictors of severe disease. The EFT is increased in HS, and it is an independent predictor of disease severity in adult patients with HS.

Isotretinoin-induced pruritic erythematous lesions and acute chest pain in a 15-year-old girl.

Isotretinoin is widely used in the treatment of acne vulgaris for more than 30 years (1). In addition to its systemic side effects, isotretinoin may also cause mucocutaneous side effects including cheilitis, nasal hemorrhage, dry skin, itching, rash, pigmented purpuric dermatosis, dry nose, purpura, and photosensitivity. We report a case of a 15-year-old girl given isotretinoin for severe acne vulgaris who developed pruritic erythematous lesions and chest pain 5 min after taking the first dose 20 mg of isotretinoin.

A condition that should be kept in mind in incarcerated hernia: Amyand's hernia.

As a complication of inguinal hernia, incarcerations are often seen in emergency services. Incarceration is an acute complication of inguinal hernia presenting as surgical emergency. The sac of inguinal hernia most frequently contains omentum and intestine but sometimes organs such as appendix and Meckel's diverticulum can also be seen in the hernial sac. We present a case of Amyand's hernia containing appendix in the incarcerated herniated sac.

Adropin as a potential marker of enzyme-positive acute coronary syndrome.

AIM: Enzyme-positive acute coronary syndrome (EPACS) can cause injury to or death of the heart muscle owing to prolonged ischaemia. Recent research has indicated that in addition to liver and brain cells, cardiomyocytes also produce adropin. We hypothesised that adropin is released into the bloodstream during myocardial injury caused by acute coronary syndrome (ACS), so serum and saliva levels rise as the myocytes die. Therefore, it could be useful to investigate how ACS affects the timing and significance of adropin release in human subjects. METHODS: Samples were taken over three days after admission, from 22 EPACS patients and 24 age- and gendermatched controls. The three major salivary glands (submandibular, sublingual and parotid) were immunohistochemically screened for adropin production, and serum and saliva adropin levels were measured by an enzyme-linked immunosorbent assay (ELISA). Salivary gland cells produce and secrete adropin locally. RESULTS: Serum adropin, troponin I, CK and CK-MB concentrations in the EPACS group became gradually higher than those in the control group up to six hours (p < 0.05), and troponin I continued to rise up to 12 hours after EPACS. The same relative increase in adropin level was observed in the saliva. Troponin I, CK and CK-MB levels started to decrease after 12 hours, while saliva and serum adropin levels started to decrease at six hours after EPACS. In samples taken four hours after EPACS, when the serum adropin value averaged 4.43 ng/ml, the receiver operating characteristic curve showed that the serum adropin concentration indicated EPACS with 91.7% sensitivity and 50% specificity, while when the cut-off adropin value in saliva was 4.12 ng/ml, the saliva adropin concentration indicated EPACS with 91.7% sensitivity and 57% specificity. CONCLUSION: In addition to cardiac troponin and CK-MB assays, measurement of adropin level in saliva and serum samples is a potential marker for diagnosing EPACS.

Laboratory markers has many valuable parameters in the discrimination between acute appendicitis and renal colic.

BACKGROUND: Only one diagnostic parameter is not available for acute appendicitis. For the establishment of diagnosis, combination of medical history, clinical, laboratory tests, and radiological imaging modalities are used so as to decrease the rates of negative laparotomy and morbidity secondary to delay in diagnosis. Thepresent study aimed to determine haematological and inflammatory markers which will be used in the discrimination of acute appendicitis (AA) and renal colic which are the most frequent and indistinguishable causes of abdominal pain in patients applying to the emergency service. METHODS: A total of 215 patients who presented with abdominal pain and who were histopathologically diagnosed as AA, and 200 patients who presented with abdominal pain and who were diagnosed as renal colic were included into the study. Control group consisted of 61 patients without any complaints who came to the outpatient clinics of internal medicine only for blood counts. Analyzed blood samples were WBC, RDW, Hb, MCV, MPV, neutrophil, lymphocyte, NLR and PLR. All differences associated with a chance probability of.05 or less were considered statistically significant. RESULTS: A statistically significant intergroup difference was seen between AA and renal colic groups as for age, WBC, Hb, MCV, neutrophil, lymphocyte, NLR and PLR. A statistically significant intergroup difference was seen between AA and control groups regarding age, WBC, Hb, RDW, MPV, neutrophil, lymphocyte, NLR and PLR. A statistically significant intergroup difference was seen between renal colic and control groups as for age, WBC, RDW, MPV, neutrophil and NLR. In ROC curve analysis, the area under AUCs for WBC, neutrophil, NLR and PLR were 0.896, 0.916, 0.888 and 0.725, respectively (p≤0.05). CONCLUSION: In the discrimination between patients with renal colic and those without any illness, WBC, RDW, MPV, neutrophil and NLR; in the differentiation between the patients with AA and healthy individuals, WBC, RDW, MPV, neutrophil, lymphocyte, NLR and PLR; and more importantly in the discrimination between patients with AA and those with renal colic who presented to emergency services with abdominal pain WBC, neutrophil, lymphocyte, PLR and NLR can be useful parameters.

The Diagnostic Role of Adiponectin in Pulmonary Embolism.

BACKGROUND AND AIMS: Pulmonary thromboembolism (PTE) is a frequent disease with difficult diagnosis and high mortality. Misdiagnosis occurs in 2/3 patients and mortality rates reach up to 30%. The aim of our study was to investigate the role of adiponectin used in emergency service in diagnosis of PTE. MATERIALS AND METHODS: 95 patients with suspected PTE included in the study. Plasma adiponectin and D-dimer levels were measured and chest X-ray and multidetector row computed tomography scan obtained. Diagnosis was supported by vascular filling defect on tomography. Control group consisted of patients with suspected PTE and normal chest computed tomography findings. RESULTS: Mean D-dimer level was 4241.66 ± 1082.98 ng/mL in patients and 2211.21 ± 1765.53 ng/mL in the control group (p ≤ 0.05). Mean adiponectin level was 5.46 ± 4.39 µg/mL in patients and 7.68 ± 4.67 µg/mL in the control group (p ≤ 0.05). Wells and Geneva scores were higher in patients compared to the control group. CONCLUSIONS: As a result, we conclude that lower adiponectin levels have an important role in the diagnosis of PTE.

The Validity of YouTube Videos on Pediatric BLS and CPR.

BACKGROUND: There are few data regarding the validity of cardiopulmonary resuscitation (CPR) and basic life support (BLS) videos on YouTube in the medical literature, and those that do are only analyzing adult CPR videos. The present study aimed to determine the reliability and accuracy of pediatric CPR and BLS videos as to whether they are consistent with the 2010 CPR guidelines. MATERIALS AND METHODS: YouTube was scanned in January 2015 using the key words "Pediatric CPR Pediatric BLS" without any filters. The raw data collected in the study included sources that uploaded the videos, the record time, the number of viewers in the study period, and inclusion of human or mannequins. Furthermore, the contents of the videos were evaluated as to whether they are consistent with the 2010 resuscitation guidelines. All videos were seen by two independent researchers (emergency physicians) and scored between 0 and 8. RESULTS: In total, 1,200 videos were evaluated regarding the exclusion criteria, which yielded 232 eligible ones. Most of the videos were found to be uploaded by individuals with unspecified credentials (34.1%). Of the videos, 15.5% have content inconsistent with the 2010 guidelines. The median score of all the videos are not high enough (5 [interquartile range (IQR), 4-7]), and only one-third of the videos have optimal quality with scores of 7 or 8. The downloaded number of videos compatible with guidelines was significantly higher relative to the videos not compatible with the guidelines (15,389 [IQR, 881-31515] versus 477 [IQR, 108-3,797); p = 0.0001). The videos downloaded more than 10,000 times had a higher score than the others (median scores of 7 and 5, respectively; p = 0.0001). CONCLUSIONS: Moderate numbers of YouTube videos purporting to be about pediatric life support have optimal quality, and few of them are perfect. Furthermore, YouTube videos uploaded by news programs with an insufficient quality have the highest download rates.

Neuron-Specific Enolase, S100 Calcium-Binding Protein B, and Heat Shock Protein 70 Levels in Patients With Intracranial Hemorrhage.

The authors evaluated neuron-specific enolase (NSE), S100 calcium-binding protein B (S100B), and heat shock protein 70 (HSP 70) levels and their relationships with in-hospital mortality, Glasgow Coma Scale (GCS) scores, and National Institute of Health Stroke Scale (NIHSS) scores. In total, 35 patients older than 18 years were presented to our emergency department and were diagnosed with non-traumatic intracranial hemorrhage (ICH) and 32 healthy controls were included. Blood samples were drawn on days 0 and 5. S100 calcium-binding protein B and HSP levels were significantly higher in patients than in controls on days 0 and 5. Neuron-specific enolase levels were higher in patients than in controls on day 0, but there was no significant difference on day 5. S100 calcium-binding protein B was negatively correlated with GCS, whereas it was positively correlated with NIHSS and bleeding volume. There was also a negative correlation between NSE and GCS, but it was not statistically significant. In addition, no significant correlation was found in terms of bleeding volume or NIHSS. Heat shock protein 70 was negatively correlated with GCS and positively correlated with bleeding volume and NIHSS, but these results were not statistically significant. S100 calcium-binding protein B and HSP 70 levels were significantly higher in those who died compared with survivors. The areas under the curve of S100 B, NSE, and HSP 70 for mortality were 0.635, 0.477, and 0.770, respectively. Neuron-specific enolase, S100B, and HSP 70 levels are simple, inexpensive, and objective measures in cases of ICH. These tests can be used to support an assessment for screening ICH patients with clinical scoring systems, such as GCS and NIHSS.

Is there a potential role for echocardiography in adult patients with CAP?

BACKGROUND: The role of echocardiography in adult patients with community-acquired pneumonia (CAP) has not been tested in a clinical trial. The aim of the study was to assess the cardiac changes secondary to CAP by echocardiography and to find out the correlation between echocardiographic findings and the severity of CAP. METHODS: A total of 111 unselected consecutive adult patients hospitalized with CAP were enrolled. The control group consisted of 100 consecutive sex- and age-matched patients. The severity of CAP was evaluated with the pneumonia severity index and the CURB-65 (confusion, urea, respiratory rate, arterial blood pressure and age) score. Blood samples were taken and echocardiography was performed within the first 48 hours. RESULTS: White blood count, N-terminal pro-brain natriuretic peptide, and red blood cell distribution width were significantly higher in the CAP group compared with the control group. The 2 groups did not differ in terms of left and right ventricle ejection fraction, left atrial diameter, pulmonary artery systolic pressure, and left ventricular end-diastolic and end-systolic diameter. However, tricuspid annular plane systolic excursion (21.1 ± 4.3 vs 22.3 ± 4.1 mm; P = .04), aortic distensibility (2.5 ± 0.9 vs 3.5 ± 0.9 cm(2):dyne:10, P < .001), and aortic strain (5.8% ± 2% vs 6.5% ± 1.9%, P = .009) were significantly reduced in CAP group than in controls. The plasma concentration of N-terminal pro-brain natriuretic peptide correlated with aortic strain, aortic distensibility, tricuspid annular plane systolic excursion, pneumonia severity index score, and CURB-65 score. CONCLUSIONS: Tricuspid annular plane systolic excursion and elastic properties of aorta may play a role in the diagnosis and clinical assessment of CAP severity, which could potentially guide the development of new prognostic models.

Paraoxonase-1 gene in patients with chronic obstructive pulmonary disease investigation Q192R and L55M polymorphisms.

BACKGROUND: The effect of increased oxidative stress on the development of chronic obstructive pulmonary disease (COPD) is well known. One of the antioxidative systems against oxidative stress in human body is paraoxonase (PON) enzyme that protects low density lipoproteins (LDL) against oxidation. This study aimed to explore the polymorphisms on PON1, Q192R, L55M genes of patients with COPD. METHODS: DNAs extraction was obtained from blood samples of 50 patients diagnosed with COPD and 50 patients as a control group who were presented to emergency clinic. Genotypes were obtained with polymerase chain reaction (PCR) and AIw I and Hsp92II restriction enzymes were used for Q192R and L55M polymorphisms, respectively. Analysis of data was done with the Chi-square test and Fisher's exact test. RESULTS: A statistically significant difference in Q192R polymorphism was found between the COPD patients and the control group (P=0.05). There was no statistically significant difference in L55M polymorphisms between the patient and control groups (P>0.05). Q192R polymorphism was significantly correlated with the PON1 gene and cigarette smoking; however other risk factors did not show any significant correlation with this polymorphism. Though L55M polymorphism was significantly correlated with family history and tuberculosis, there was no significant correlation with other risk factors. CONCLUSION: We believe that more studies are needed to study the correlation of L55M polymorphism with other factors.