ABSTRACT
This study aimed to explore the role of the cerebellum on the somatosensory temporal discrimination (STD) process. Twenty healthy volunteers were enrolled in the study. Each participant was included in three different transcranial direct current stimulation (tDCS) sessions as anodal, cathodal, and sham sessions in randomised order. Anodal and cathodal cerebellar tDCS (cTDCS) were given for 20 min at an intensity of 2 mA. The results of the study indicate no effect of cTDCS on STD. Although the study results show that cTDCS does not affect STD, because of the restricted sample size of the study, it is useful and necessary to investigate this relationship more in depth in a larger healthy subject population using different cTDCS methodologies.
Subject(s)
Sexually Transmitted Diseases , Transcranial Direct Current Stimulation , Humans , Cerebellum/physiology , Healthy Volunteers , Transcranial Direct Current Stimulation/methodsABSTRACT
BACKGROUND: Coronavirus disease 2019 (COVID-19) pandemic and lockdown period may induce an impairment in quality of life (QoL), disruption in treatment (DIT), and posttraumatic stress disorder (PTSD) in chronic neurological diseases (CNDs). To reach this information, a multicenter, cross-sectional study (COVQoL-CND) was planned. Parkinson's disease (PD), headache (HA), multiple sclerosis (MS), epilepsy (EP), polyneuropathy (PNP), and cerebrovascular disease (CVD) were selected as the CND. METHODS: The COVQoL-CND study includes demographic data, the World Health Organization Quality of Life short form (WHOQOL-BREF), and Impact of Event Scale-Revised (IES-R) forms. RESULTS: The mean age of a total of 577 patients was 49 ± 17 (19-87 years), and the ratio of female/male was 352/225. The mean age of patients with PD, HA, MS, EP, PNP, and CVD were 65 ± 11, 39 ± 12, 38 ± 10, 47 ± 17, 61 ± 12, and 60 ± 15 years, respectively. The IES-R scores were found to be higher in the younger group, those with comorbid disease, contacted with CO-VID-19 patients, or diagnosed with COVID-19. In the group with a high IES-R score, the rate of DIT was found to be high. IES-R scores were negatively correlated with QoL. IES-R total scores were found highest in the CVD group and lowest in the PD group. The ratio of DIT was found highest in the PNP group and the lowest in the EP group. Contact with CO-VID-19 patients was high in the EP and HA group. CONCLUSIONS: The results of the COVQoL-CND study showed that lockdown causes posttraumatic stress and deterioration in the QoL in CND.
Subject(s)
COVID-19 , Quality of Life , Adult , Aged , Aged, 80 and over , Communicable Disease Control , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , SARS-CoV-2 , Surveys and Questionnaires , Young AdultABSTRACT
Background and objectives: Hypertension is a global health problem and a major risk factor for cardiovascular diseases. Vitamin D deficiency is closely related to high blood pressure and the development of hypertension. This study investigated the relationship between the vitamin D and blood pressure status in healthy adults, and their 8-year follow-up was added. Materials and Methods: A total of 491 healthy middle-aged participants without any chronic illness, ages 21 to 67 at baseline, were divided into two groups as non-optimal blood pressure (NOBP) and optimal blood pressure (OBP). NOBP group was divided into two subgroups: normal (NBP) and high normal blood pressure (HNBP). Serum 25-hydroxy vitamin D levels were measured with the immunoassay method. 8-year follow-up of the participants was added. Results: The average vitamin D level was detected 32.53 ± 31.50 nmol/L in the OBP group and 24.41 ± 14.40 nmol/L in the NOBP group, and a statistically significant difference was found (p < 0.001). In the subgroup analysis, the mean vitamin D level was detected as 24.69 ± 13.74 and 24.28 ± 14.74 nmol/L in NBP and HNBP, respectively. Together with parathyroid hormone, other metabolic parameters were found to be significantly higher in the NOBP. During a median follow-up of 8 years, higher hypertension development rates were seen in NOBP group (p < 0.001). Conclusions: The low levels of vitamin D were significantly associated with NBP and HNBP. The low levels of vitamin D were also associated with the development of hypertension in an 8-year follow-up.
Subject(s)
Hypertension , Vitamin D Deficiency , Adult , Aged , Blood Pressure , Calcifediol , Humans , Hypertension/epidemiology , Hypertension/etiology , Middle Aged , Parathyroid Hormone , Vitamin D , Vitamin D Deficiency/complications , Vitamin D Deficiency/epidemiology , Young AdultABSTRACT
Motor cortex activity level is a critical part of the effect of transcranial direct current stimulation (tDCS) on corticomotor excitability. Based on homeostatic plasticity, the state of the stimulated cortical area influences the direction of neuroplastic changes induced by stimuli. Owing to homeostatic plasticity, cathodal tDCS (c-tDCS) would likely have a pronounced inhibitory effect on corticomotor excitability during a motor task, compared with the resting state. To test this hypothesis, we detected motor evoked potential (MEP) amplitude changes before and during c-tDCS with voluntary movement. Twelve healthy right-handed volunteers (9 males, 27-48 years) were enrolled in the study. Subjects performed little finger abduction motor task. Passive (APB) and active (ADM) muscles were studied. MEP amplitudes were measured during resting (baseline) and movement stages, and subsequently with the contralateral M1 modulated by c-tDCS. c-tDCS caused reduced baseline MEP amplitude in the ADM (p < 0.05) and APB (p < 0.001) muscles. Sham stimulation had no effect on the baseline MEP amplitudes. MEP amplitude ratio (MEP amplitude triggered by movement/baseline MEP amplitude) was higher during c-tDCS than before c-tDCS (p < 0.01). Our results suggested that during voluntary contraction, c-tDCS has an opposite effect on corticospinal excitability compared with resting state modulation effect. This contrast effect could be related to modulation of movement preparation and execution.
Subject(s)
Evoked Potentials, Motor/physiology , Motor Activity/physiology , Motor Cortex/physiology , Muscle, Skeletal/physiology , Transcranial Direct Current Stimulation/methods , Transcranial Magnetic Stimulation/methods , Adult , Electrodes , Electromyography , Female , Fingers/physiology , Humans , Male , Middle AgedABSTRACT
Vaspin, a recently identified adipokine, is a visceral adipose tissue-derived serine protease inhibitor that may have insulin sensitizing effect on adipose tissue. Herein, we measured vaspin level in patients with different stages of diabetic nephropathy (DNP), and investigated the correlation of the vaspin level with other inflammatory parameters. 106 adult type 2 diabetic patients with no known chronic inflammatory disease were included and grouped according to the stage of DNP: Albuminuria <30 mg/day and estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73m(2) (Group-1); albuminuria 30-300 mg/day and eGFR >60 mL/min/1.73m(2) (Group-2); albuminuria >300 mL/min and eGFR <60 mL/min/1.73m(2) (Group-3). Demographic, clinical and laboratory data were recorded as well as vaspin, high sensitivity C-reactive protein (hsCRP), interleukin (IL)-1 and tumor necrosis factor (TNF)-α levels. There were 38, 35 and 33 patients in Group 1, 2 and 3, respectively. Groups were similar regarding age and gender. Vaspin level did not differ between groups. When all the groups were considered, vaspin was positively correlated with IL-6 level (r = 0.215, p = 0.041). No correlation of vaspin was found with IL-1, TNF-α and hsCRP levels (p = 0.580, r = 0.054; p = 0.463, r = 0.072; p = 0.812, r = 0.025, respectively). Vaspin levels of the patients with GFR ≥60 mL/min/1.73m(2) was less than that of patients with GFR <60 mL/min/1.73m(2) (p = 0.03). Age and IL-6 were found to be the major determinants of vaspin level with linear regression analysis. In patients with DNP, vaspin level does not change within the early stages of DNP; while it is higher in patients with decreased GFR, which may be related with increasing inflammation regardless of the stage of the kidney disease.
Subject(s)
Adipokines/blood , Diabetes Mellitus, Type 2/complications , Diabetic Nephropathies/blood , Inflammation/blood , Interleukin-6/blood , Serpins/blood , Age Factors , Albuminuria/urine , Biomarkers/blood , C-Reactive Protein/analysis , Cross-Sectional Studies , Diabetic Nephropathies/classification , Diabetic Nephropathies/etiology , Female , Glomerular Filtration Rate , Humans , Insulin Resistance , Interleukin-1/blood , Male , Middle Aged , Tumor Necrosis Factor-alpha/bloodABSTRACT
Resective epilepsy surgery has been accepted as an effective treatment for patients with medically intractable temporal lobe epilepsy (TLE) to control the seizures and to limit cognitive dysfunction. Complete resection of the epileptic zone, and therefore the success of the surgery, depends on the identification of the seizure focus. Reliable lateralizing semiologic signs, together with other presurgical assessments, are of great importance for an accurate identification of the seizure focus. In this respect, this study evaluated the frequency of semiologic signs in medically intractable temporal lobe epilepsy (TLE) together with the lateralizing values and variations according to the age and gender groups. Two hundred seventy-three seizures of 55 patients of the Adult Epilepsy Monitoring Unit of Gazi University Faculty of Medicine with the diagnosis of medically intractable TLE, whose epileptic foci were detected through noninvasive presurgical procedures and seizures were controlled successfully after anterior temporal lobectomy (ATL), were analyzed retrospectively. Seizure semiologies of the patients were evaluated in terms of lateralizing values, and it was inquired whether age/gender causes any variation. Versive head rotation, unilateral dystonic limb posturing, asymmetric tonic limb posturing, and the combination of unilateral hand automatisms and dystonic posturing were determined as the semiologic signs with the highest lateralizing values (90-100%). While hand automatisms were observed frequently in the group with early seizure-onset age (onset age ≤ 2), asymmetric tonic limb posturing was detected as more frequent in the group with later seizure-onset age (onset age > 2; p < .005). In addition to this, semiologic signs were noted to be different between male and female groups; psychic and autonomic auras and ictal emotional signs were associated with women (p < .005).
Subject(s)
Epilepsy, Temporal Lobe/physiopathology , Functional Laterality , Adolescent , Adult , Age of Onset , Anterior Temporal Lobectomy , Autonomic Nervous System/physiopathology , Disease Progression , Drug Resistant Epilepsy/physiopathology , Drug Resistant Epilepsy/psychology , Drug Resistant Epilepsy/surgery , Electroencephalography , Emotions , Epilepsy, Generalized/physiopathology , Epilepsy, Temporal Lobe/psychology , Epilepsy, Temporal Lobe/surgery , Female , Humans , Male , Middle Aged , Neurosurgical Procedures , Posture , Retrospective Studies , Sex Characteristics , Young AdultABSTRACT
BACKGROUND: The presence of notched R or S waves without accompanying typical bundle branch blocks, or the existence of an additional wave like RSR' pattern in the original QRS complex (with a duration of <120 ms) has been defined as narrow QRS fragmentation. Persistence of the fQRS found on the admission electrocardiogram (ECG) in patients with acute ST segment elevation myocardial infarction (STEMI) will have prognostic significance in the short term. METHODS: The study was carried out using retrospectively collected data of 296 consecutive patients diagnosed as acute STEMI .fQRS group had fQRS both in admission and latest ECGs (n = 80, 27%), and non-fQRS group had no fQRS in last ECG (n = 216, 73%). Primary end points were in-hospital cardiovascular mortality, hemodynamic instability, and electrical instability. RESULTS: MI localization, symptom duration, reperfusion therapy (RPT) rate, RPT modality, rate of successful reperfusion did not differ. Mean ejection fraction was lower and all end points were more frequent in the fQRS group. Irrespective of the RPT modality and success of RPT, mortality rate was higher in patients with persistent fQRS. GRACE score >120 points (OR = 4.765), age >70 years (OR = 4.041), anterior MI localization (OR = 3.148), and presence of fQRS (OR = 2.484) were significant predictors of primary end points. fQRS increased the predictive ability of GRACE score >120 about two folds (OR = 7.305, P < 0.001). CONCLUSION: Persistent fQRS on ECG is associated with poor prognosis and there is a lack of expected mortality benefit of RPT, particularly that of fibrinolytic therapy, in STEMI patients with fQRS.
Subject(s)
Arrhythmias, Cardiac/diagnosis , Electrocardiography , Heart Conduction System/abnormalities , Myocardial Infarction/physiopathology , Aged , Arrhythmias, Cardiac/mortality , Arrhythmias, Cardiac/physiopathology , Brugada Syndrome , Cardiac Conduction System Disease , Female , Heart Conduction System/physiopathology , Hemodynamics , Hospital Mortality , Humans , Male , Middle Aged , Myocardial Infarction/mortality , Myocardial Infarction/therapy , Predictive Value of Tests , Prognosis , Retrospective Studies , Risk FactorsABSTRACT
BACKGROUND: The present study aimed to evaluate resting middle cerebral artery (MCA) blood flow velocities using transcranial Doppler ultrasound (TCD) in healthy women at different stages of pregnancy, and to compare these velocities with those of normal controls. METHODS: A total of 105 healthy normotensive pregnant women and 25 non-pregnant healthy controls were included in the study. We formed 3 groups according to gestational age: first trimester (7 to 13 wk pregnant), second trimester (14 to 28 wk pregnant), and third trimester (29 to 42 wk pregnant). Age, body mass index, heart rate, arterial blood pressure, and hematological data were recorded and TCD was performed on the subjects. Regarding TCD, we evaluated the mean cerebral blood flow velocity, the peak systolic velocity, the end-diastolic flow velocity, S/D ratio, the pulsatility Index (PI) and the resistance Index (RI). RESULTS: The MCA mean blood flow velocities differed significantly among the groups ( P <0.001) and were higher in the controls than those of the first trimester, second trimester, and third trimester groups ( P <0.01, P <0.001, P <0.001 respectively). The MCA mean and peak blood flow velocities, and the PI and RI decreased significantly with advancing gestation. CONCLUSIONS: TCD is a noninvasive and non-toxic method of monitoring the adaptation of the maternal cerebral blood flow in pregnancy. The progressive decreases in the MCA mean and peak blood flow velocities, PI, and RI during gestation may be the result of chemical and neuronal factors. This study supports the need for additional studies using TCD to establish normative cerebral blood flow volumes throughout pregnancy.
Subject(s)
Cerebrovascular Circulation , Middle Cerebral Artery , Pregnancy , Humans , Female , Blood Flow Velocity/physiology , Middle Cerebral Artery/diagnostic imaging , Blood Pressure/physiology , Cerebrovascular Circulation/physiology , Ultrasonography, Doppler, TranscranialABSTRACT
OBJECTIVE: To determine whether alterations in pulmonary function takes place in subclinical hypothyroidism by examining the diffusion lung capacity and muscle strength of such patients. METHODS: This is a descriptive study conducted in 2009 at Haseki Training and Research Hospital, Istanbul, Turkey. Hundred and twenty-six patients with subclinical hypothyroidism and 58 age and sex matched individuals were recruited. Simple spirometry tests were performed, and pulmonary diffusion capacity (DLco) and muscle strength were measured. RESULTS: ScH patients showed a significant reduciton of the following pulmonary function tests (% predicted value) as compared with control subjects: FVC, FEV1, FEV1%, FEF25-75, FEF25-75%, DLco, DLco/VA, Pimax, Pimax% and Pemax%. CONCLUSION: These data indicate that pulmonary functions are effected in subclinical hypothyrodism. Therefore patients with or who are at high risk of having subclinical hypothyroidism, should be subjected to evaluation of pulmonary functions with simple spirometry.
Subject(s)
Hypothyroidism/physiopathology , Lung/physiopathology , Muscle Strength , Pulmonary Diffusing Capacity , Adult , Case-Control Studies , Female , Humans , Male , Middle Aged , Severity of Illness Index , Spirometry/methodsABSTRACT
OBJECTIVE: This prospective observational study aimed to identify the effects of labor on cerebral hemodynamics by measuring the middle cerebral artery (MCA) blood flow velocity by transcranial Doppler ultrasound (TCD), and the related factors just before delivery and within the 24 h after delivery. METHODS: The study included 35 healthy pregnant women with a gestational age of >37 weeks who were in labor and a control group including healthy, age-matched, nonpregnant women (n = 24). Demographic characteristics and significant clinical information of pregnant women were recorded. The MCA blood flow velocity was assessed by TCD just before and within 24 h after delivery. The parameters assessed by TCD were mean cerebral blood flow velocity (MCBFV), peak systolic velocity (PSV), pulsatility index (PI), resistance index (RI), and systolic/diastolic ratio. RESULTS: There was no significant difference between the pregnant and nonpregnant women regarding age (27 ± 5 years versus 28 ± 7 years; p = .751). The MCBFV, PSV, PI, and RI showed a significant increase within the 24 h after delivery as compared with those before delivery. Comparison of the pregnant women with the control group in terms of the values of all parameters related to the MCA blood flow velocity revealed that the values that were significantly low before delivery reached to the level of the control group after delivery Conclusion: The findings of this study demonstrated that the blood flow velocity of the MCA decreased during the late pregnancy period and increased in the early postpartum period to the level similar to that of the nonpregnant group.
Subject(s)
Blood Flow Velocity/physiology , Labor, Obstetric/physiology , Middle Cerebral Artery/physiology , Pregnancy/physiology , Adult , Case-Control Studies , Cerebrovascular Circulation/physiology , Female , Humans , Middle Cerebral Artery/diagnostic imaging , Postpartum Period/physiology , Pregnancy Trimester, Third/physiology , Prospective Studies , Ultrasonography, Doppler, Transcranial , Young AdultABSTRACT
Background/aim: In parallel with increased frequency and higher quality of imaging techniques, the prevalence of adrenal adenoma has gradually increased. However, despite the growing incidence, the metabolic and tumorigenesis processes involved in its etiology are still unclear. Although visfatin has been reported to be associated with inflammation and tumorigenesis, its role in adrenal adenoma has not yet been investigated. Therefore, the present study was performed with an aim to evaluate visfatin levels and cardiometabolic risk factors in patients with adrenal adenoma. Materials and methods: Thirty patients recently diagnosed with adrenal adenoma along with 30 healthy participants were studied in a tertiary healthcare center. Twenty-four-hour ambulatory blood pressure monitoring and carotid artery intima-media thickness (CIMT) measurements were performed. Results: The frequencies of diabetes mellitus and hypertension were found to be statistically higher in the adrenal adenoma group. Although the values of mean fasting glucose, insulin, HOMA-IR levels, and the mean, maximum, minimum, delta systolic, and diastolic blood pressures were established to be higher in the adrenal adenoma group, the differences were not found to be statistically significant. Mean high-sensitive C-reactive protein, visfatin levels, and CIMT were seen to be significantly higher in the adenoma group. Conclusion: Cardiometabolic risk factors as well as the visfatin levels were established to be higher in patients with adrenal adenoma. Elevated visfatin levels might play a role in the development and metabolic process of adrenal adenoma.
ABSTRACT
Excess N-terminal pro-brain natriuretic peptide secretion has been linked to cirrhosis in previously studies. The relationship of plasma N-terminal pro-brain natriuretic peptide levels and cardiac dysfunction determined by echocardiography were investigated in patients with nonalcoholic cirrhosis and a control group of chronic hepatitis. This study was designed as a cross-sectional study. Thirty-two men and thirty-three women who gave informed consent who were followed-up for chronic liver failure were enrolled. All patients gave clinical history, physical examination was carried out and information about ongoing medication has been obtained. Serum N-terminal pro-brain natriuretic peptide level was measured in all patients. The same cardiologist determined ejection fraction, end-diastolic left ventricular diameter, interventricular septum, and posterior wall on transthoracic echocardiography. Patients with extensive liver disease according to Child-Pugh classification from A to C had increasing N-terminal pro-brain natriuretic peptide levels in association (P < .001). According to the Child-Pugh classification there were no significant difference between groups for echocardiographic measurements (P > .05). N-terminal pro-brain natriuretic peptide may be an important marker for cardiac dysfunction in patients with chronic liver failure in accordance with Child-Pugh stage.
Subject(s)
Liver Cirrhosis/blood , Natriuretic Peptide, Brain/blood , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers/blood , Cross-Sectional Studies , Female , Heart Diseases/blood , Humans , Liver Cirrhosis/diagnosis , Male , Middle Aged , Severity of Illness Index , Young AdultABSTRACT
BACKGROUND: Sjögren syndrome (SS) is an autoimmune-lymphoproliferative disorder characterized by mononuclear cell infiltration of exocrine glands. Clinically, Sjögren syndrome (SS) has a wide spectrum, varying from autoimmune exocrinopathy to systemic involvement. There have been few cases reporting that primary SS developed with distal renal tubular acidosis clinically. CASE REPORT: Here, we present a case with primary Sjögren syndrome accompanied by hypopotassemic paralysis due to renal tubular acidosis. Severe hypopotassemia, hyperchloremic metabolic acidosis, alkaline urine and disorder in urinary acidification test were observed in the biochemical examination of the 16-year-old female patient, who had applied to our clinic for extreme loss of muscle force. After the examinations it was determined that the patient had developed Type 1 RTA (distal RTA) due to primary Sjögren syndrome. Potassium and alkaline replacement was made and an immediate total recovery was achieved. CONCLUSIONS: Hypopotassemic paralysis due to primary Sjögren syndrome is a rare but severe disorder that could lead to death if not detected early and cured appropriately. Thus, effective treatment should be immediately initiated in cases where severe hypopotassemia is accompanied by metabolic acidosis, and the cases should also be examined for extraglandular involvement of SS.
ABSTRACT
BACKGROUND: Metabolic syndrome is associated with cardiovascular disease and oxidative stress. The aim of this study was to investigate the differences of novel oxidative stress parameters and lipid profiles in men and women with metabolic syndrome. METHODS: The study population included 88 patients with metabolic syndrome, consisting of 48 postmenauposal women (group I) and 40 men (group II). Premenauposal women were excluded. Plasma levels of total antioxidant status (TAS) and total oxidative status (TOS) were determined by using the Erel automated measurement method, and oxidative stress index (OSI) was calculated. To perform the calculation, the resulting unit of TAS, mmol Trolox equivalent/L, was converted to micromol equivalent/L and the OSI value was calculated as: OSI = [(TOS, micromol/L)/(TAS, mmol Trolox equivalent/L) x 100]. The Student t-test, Mann-Whitney-U test, and chi-squared test were used for statistical analysis; the Pearson correlation coefficient and Spearman rank test were used for correlation analysis. P < or = 0.05 was considered to be statistically significant. RESULTS: Both women and men had similar properties regarding demographic characteristics and biochemical work up. Group II had significantly lower levels of antioxidant levels of TAS and lower levels of TOS and OSI compared with group I (P = 0.0001, P = 0.0035, and P = 0,0001). Apolipoprotein A (ApoA) levels were significantly higher in group I compared with group II. CONCLUSIONS: Our findings indicate that women with metabolic syndrome have a better antioxidant status and higher ApoA levels compared with men. Our findings suggest the existence of a higher oxidative stress index in men with metabolic syndrome. Considering the higher risk of atherosclerosis associated with men, these novel oxidative stress parameters may be valuable in the evaluation of patients with metabolic sydrome.
Subject(s)
Metabolic Syndrome/blood , Aged , Antioxidants/metabolism , Apolipoproteins A/metabolism , Automation , Female , Humans , Hypertension , Male , Metabolic Syndrome/diagnosis , Metabolic Syndrome/epidemiology , Middle Aged , Models, Biological , Obesity , Oxidative Stress , Postmenopause , Sex FactorsABSTRACT
OBJECTIVE: The current study was conducted to determine whether or not the lung is one of the target organs in the development of vascular complications in diabetic patients. We also investigated the relationship between pulmonary diffusing capacity and microalbuminuria. MATERIALS AND METHODS: A total of 68 patients with type 2 diabetes and 44 with type 1 diabetes (male/female [M/F] n=19/49 and 15/29; age: 52.4+/-8.8 and 32.5+/-11 years;) and 80 healthy controls (M/F=22/58; age=40.1+/-12.4 years) were recruited for the study. All of the participants were evaluated with simple spirometric tests and a simple breath carbon monoxide (CO) diffusion test. CO lung diffusion capacity (DLCO) and the ratio of DLCO value to the alveolar volume (VA) were used to assess alveolar membrane permeability (DLCO/VA). Urinary albumin excretion (UAE) per day of the participants was also evaluated. RESULTS: DLCO, DLCO% and DLCO/VA% values were significantly lower in diabetics than in the control group (p=0.006; p=0.039; p=0.003, respectively). UAE was inversely correlated with DLCO, DLCO/VA, DLCO/VA% and DLCO% (p=0.050; p=<0.001; p=0.001; p=0.004, respectively). CONCLUSION: This study demonstrated that alveolar gas exchange capacity is significantly decreased in diabetic patients. Microalbuminuria may be one of the predictors of this decline.