Prosthetic Rehabilitation with Implant-Supported Mandibular Overdenture after Partial Glossectomy and Radiation Therapy: A Case Report.

Implant-supported overdenture is a well-established treatment option for many patients who have functional problems with conventional dentures. It may be primary choice for patients with altered jaw anatomy, neuromuscular disorders, pronounced gag reflex, severe residual ridge resorption and oral tissue defects. In this article we describe a case report, where tongue cancer patients occlusion was rehabilitated with an implantretained overdenture. In 2001 patient was operated for squamous cell carcinoma on the left side of the tongue. Before preoperative radiation therapy, small residual mandibular dentition was removed because of its poor prognosis. Radiation dose on mandible was 57-66 Gy. After tumor surgery patient received conventional complete dentures. Ten years later, the patient was referred again to the Turku University Central Hospital due to constant ulceration under the mandibular denture. The residual ridge of the mandible was severely resorbed. Patient's existing lower complete denture was replaced with a milled bar-retained overdenture on four implants. Treatment turned out to be challenging due to severely restricted tongue movement and tissue defects.

Reproducibility of Tract-based and Region-of-Interest DTI Analysis of Long Association Tracts.

PURPOSE: Reproducibility of two different methods for quantifying fiber tracts by using a diffusion tensor imaging (DTI) sequence suitable for clinical magnetic resonance imaging (MRI) protocols was evaluated. METHODS: DTI of 15 subjects was used to analyze intra-rater and inter-rater reproducibility. Another 10 subjects underwent MRI twice for assessment of between-scan reliability. Ten long association tracts were defined by fiber tracking using inclusion and exclusion regions of interest (ROIs). Whole-tract analysis and tractography-based core analysis were performed, and the effect of fractional anisotropy (FA 0.15/0.30) and turning angle threshold (27°/60°) on reproducibility was evaluated. Additionally, ROI measurements were performed in the core of the tracts. RESULTS: For the tract-based methods, intra-rater and inter-rater reliabilities of FA and mean diffusivity (MD) measurements were excellent. Between-scan reproducibility was good or excellent in 127 of 130 of the measurements. There was no systematic difference in the reproducibility of the FA, MD, and volume measurements depending on the FA or turning angle threshold. For the cross-sectional ROI measurements, reliability showed large variation from poor to excellent depending on the tract. CONCLUSIONS: Compared with the commonly used cross-sectional core ROI method, the tract-based analyses seem to be a more robust way to identify and measure white matter tracts of interest, and provide a novel reproducible tool to perform core analysis.

Diffusivity of normal-appearing tissue in acute traumatic brain injury.

BACKGROUND: Apparent diffusion coefficient (ADC) values derived from diffusion-weighted magnetic resonance imaging (MRI) can provide information about traumatic changes not visible in conventional MRI. The ADC values in acute traumatic brain injury (TBI) were measured and correlated with initial severity and outcome scores. METHODS: In this study 22 unselected patients were studied 1 week (mean 7 ± 2 days) after TBI of variable severity. In conventional MRI 7 patients were without visible findings, 15 showed cortical contusions or traumatic axonal injury and 14 healthy subjects served as controls. The ADC values were measured from 46 brain regions away from the visible traumatic changes and compared between the groups. Regional ADC values and the number of abnormal regions were correlated with the Glasgow coma scale (GCS) on arrival in hospital and the Glasgow outcome scale (extended version, GOS-E) at 1 year after injury. RESULTS: The ADC values of TBI patients with and without visible lesions did not show any differences but both groups differed significantly from the controls in several cortical and deep brain regions. Increased ADC values were common in TBI groups but decreased ADC values were relatively uncommon. The regional ADC values and the number of abnormal regions did not correlate with either GCS or GOS-E scores. CONCLUSIONS: Increased diffusion in normal appearing brain tissue is a common finding 1 week after TBI in patients with and without visible lesions in conventional MRI. More investigations are needed to evaluate how these findings could be used for clinical applications.

Apparent Diffusion Coefficient Histograms in the Follow-up of Relapsing-Remitting Multiple Sclerosis.

Diffusion-weighted (DW) magnetic resonance (MR) imaging in addition to conventional magnetic resonance MR images provide valuable information in multiple sclerosis (MS). Increased diffusivity measured with diffusion-weighted imaging (DWI) has been demonstrated in normal appearing brain tissue in MS. So far, longitudinal changes taking place in whole-brain histograms in patients with active relapsing-remitting MS have not been evaluated. The aim of this study was to evaluate how apparent diffusion coefficient (ADC) histograms are altered during the follow-up of active relapsing-remitting MS patients. Nine patients were studied twice by MRI with a three-month interval. All patients had active newly diagnosed MS with two to three relapses during the year preceding the first MRI, and interferon-beta treatment was initiated after obtaining the first image. ADC histograms were produced after removing extracranial tissues and cerebrospinal fluid from the images. Additionally, brain volume index (BVI) and lesion volume on FLAIR images were measured. Five patients had signs of disease activity in the follow-up MRI. In the four patients without signs of disease activity the change in ADC histogram parameters was less than 2%. In patients with disease activity both increase (one case) and decrease (four cases) in histogram parameters were detected. Changes in BVI or lesion volume did not significantly correlate with histogram changes. The number of new T2-lesions showed a positive correlation with mean (r=0.79, P=0.014) and upper quartile (r=0.77, P=0.021) value change. Alterations in disease activity lead to histogram changes; both shifts to lower values and shifts to higher values are possible. The histogram changes are mostly related to subtle inflammatory changes in normal appearing brain tissue during inflammatory activity and their resolution during less active inflammatory conditions.

Magnetic resonance imaging of the brain used to detect early post-partum activation of multiple sclerosis.

Post-partum relapses are a frequent phenomenon in multiple sclerosis (MS). The purpose of this study was to evaluate the timing and extent of new or growing T2-lesions after delivery in a cohort of Finnish MS patients. In addition to serial magnetic resonance imaging (MRI), the patients were followed up clinically with determination of relapse rate and expanded disability status scale. The annualized relapse rate was decreased during the last trimester of pregnancy [mean 0.14, standard deviation (SD) 0.14] when compared with the time before pregnancy (mean 0.64, SD 0.14; P = 0.04) and to time post-partum (mean 1.50, SD 0.45; P = 0.0002). New or enlarging lesions were detected in the post-partum images in 14 of 28 patients. Gadolinium-enhancing lesions in post-partum MRI were present in eight of 13 patients. There was a significant increase in the number of T2-lesions (P = 0.0009), in the total volume of MS-lesions measured from fluid-attenuated inversion recovery images (P = 0.0126) and in the number of diffusion weighted imaging hyperintense lesions (P = 0.0098) in the post-partum images. The clinical results support the earlier findings of decreased disease activity in late pregnancy. The clinical and MRI findings indicate that post-partum activation is an early and common phenomenon amongst mothers with MS.

Hippocampal volume, brain atrophy, and APOE genotype after traumatic brain injury.

OBJECTIVE: To examine the association between hippocampal volumes, general brain atrophy, and apolipoprotein E (APOE) polymorphism in patients with a remote traumatic brain injury (TBI). METHODS: MRI-based volumetric analyses of the hippocampus and lateral ventricles were performed in 58 patients with TBI of varying severity on average 31.3 years after the trauma. The APOE genotype was determined using standard methods and correlated with the MRI volumetric measurements. RESULTS: Hippocampal or lateral ventricle volumes did not differ significantly in those patients with the APOE-epsilon4 allele (APOE4) vs those without this allele. CONCLUSIONS: The APOE-epsilon4 allele was not associated with the development of hippocampal or ventricular atrophy after traumatic brain injury. If the APOE-epsilon4 allele is associated with an unfavorable outcome after traumatic brain injury as proposed, this association may involve mechanisms other than those responsible for the development of brain atrophy.

Longitudinal cognitive changes in traumatic brain injury: a 30-year follow-up study.

OBJECTIVE: To evaluate longitudinal cognitive changes in patients over three decades following traumatic brain injury (TBI). METHOD: Two hundred ten patients with substantial TBI of variable severity were initially assessed between 1966 and 1972 at Turku University Hospital (Finland). Of these, 61 patients could be studied using the same assessments in the follow-up examination, on average 30 years after the TBI. The results of the follow-up assessment were also compared with an age- and education-matched control group. During each examination, patients were assessed with five subtests of the Wechsler Adult Intelligence Scale, three tests for episodic memory, and the general cognitive decline was determined. RESULTS: The general pattern of slight cognitive decline during a 30-year follow-up contrasted with improvement in semantic memory. Women maintained their cognitive level, but men showed a decline during the follow-up, especially in visuospatial ability and visual memory. Younger patients were likely to maintain or even improve their cognitive functioning. CONCLUSIONS: Most of the patients had mild cognitive decline during the follow-up, but this decline was influenced by gender and age at injury. Unlike the long-term course in the other domains of cognition, semantic memory showed good recovery potential after traumatic brain injury (TBI). The profile of long-term cognitive decline after TBI seems to be qualitatively different from the early signs of dementia of the Alzheimer type.

Mapping brain structure and personality in late adulthood.

Cerebral gray matter (GM) volume decreases in normal aging with a parallel increase in intracranial cerebrospinal fluid (CSF) volume. There is considerable interindividual variation in these changes, and the consequences of age-related GM shrinkage and CSF expansion are unclear. The present study examined whether late adulthood brain structural differences are related to differences in temperament and character. Personality structures of 42 healthy aged adults (mean age 60 years) were examined together with global and regional GM, CSF, and white matter (WM) volumes calculated from structural magnetic resonance images using voxel-based morphometry (VBM). A positive relationship was seen between GM volume at the border of the temporal, parietal, and frontal cortices, and self-transcendence, a character personality trait that reflects mature creativity and spiritualism. The relationship remained significant after a conservative correction for multiple comparisons and it was seen both using uncorrected raw values and after a correction for the effects of age and sex. The results suggest that high self-transcendence, which has adaptive advantages in the later part of life, is associated with relatively greater temporal cortical GM volumes.

Hippocampal and prefrontal atrophy in patients with early non-demented Parkinson's disease is related to cognitive impairment.

BACKGROUND: Early stage patients with Parkinson's disease (PD) show cognitive impairment in frontal lobe functions and memory tests. Hippocampal atrophy is seen in medicated patients with advanced PD. OBJECTIVES: To examine whether prefrontal or hippocampal atrophy are already present in early stage PD, and whether such atrophy is associated with cognitive impairment. METHODS: Twenty non-medicated, non-demented patients with early stage PD and 22 neurologically healthy age matched controls were studied. All subjects underwent magnetic resonance imaging to study hippocampal and prefrontal atrophy. Atrophy was evaluated by a neuroradiologist using a five point scale. In addition, the patients underwent a neuropsychological test battery sensitive to frontal lobe functions and memory. RESULTS: Patients with PD had atrophy in the right and the left prefrontal cortex. In the right hippocampus, the mean atrophy score was 1.15 in PD and 0.45 in controls. Corresponding figures for the left hippocampus were 1.05 for PD and 0.64 for controls. In PD, the left hippocampus atrophy correlated with verbal memory and prefrontal atrophy correlated with impaired performance in a test measuring vigilance. CONCLUSIONS: Non-medicated, non-demented patients with early stage PD show hippocampal and prefrontal atrophy. Impaired memory is related to hippocampal atrophy, whereas sustained attention is related to prefrontal atrophy.

Hippocampal MRI volumetry in cognitively discordant monozygotic twin pairs.

OBJECTIVE: To investigate whether hippocampal atrophy, a proxy for incipient Alzheimer's disease, can be detected in non-demented monozygotic co-twins of demented twins by using volumetric magnetic resonance imaging (MRI). METHODS: Seven pairs of monozygotic female twins discordant for cognitive function (mean (SD) age 75 (4) years), and 10 age and education matched healthy controls (seven women, three men; mean age 73 (3) years) were studied with volumetric MRI. RESULTS: The mean normalised right hippocampal volume was 31% lower (p = 0.002) in the demented twins, and 6% lower (p = 0.45) in the non-demented twins than in the controls. In the left hippocampus, the mean normalised volume was 36% lower (p<0.001) in the demented twins, and 9% lower (p = 0.13) in the non-demented twins than in the controls. CONCLUSIONS: Significant hippocampal atrophy was detected in the demented twins compared with the controls. This is in line with previous imaging and pathological studies, with hippocampus showing the early changes in Alzheimer's disease. In the non-demented twins, only a minor, non-significant reduction was observed in the hippocampal volumes compared with the controls. This could reflect gene-environment interactions that have protected the non-demented twins longer than their demented co-twins and contributed to the relative preservation of their hippocampal volumes, or it could be a sign of preclinical Alzheimer's disease in the non-demented twins.

Hippocampal dopamine D2 receptors correlate with memory functions in Alzheimer's disease.

Post mortem studies have revealed a loss of dopamine D2 receptors in the temporal lobes in Alzheimer's disease (AD). Moreover, the role of hippocampal D2 receptors on memory performance has been suggested in experimental studies. However, there are no previous in vivo studies on extrastriatal D2 receptors in AD. Our aim was to examine in vivo whether hippocampal or temporal cortical dopamine D2 receptors are affected in AD and whether D2 receptor availability is associated with the memory dysfunction seen in AD. Fourteen patients with probable AD and 11 age- and sex-matched controls were studied with positron emission tomography using a dopamine D2/D3 receptor antagonist [(11)C]FLB 457. The D2 receptor binding potentials (BPs) were measured in extrastriatal brain regions and a neuropsychological investigation was performed on the patients with AD. In AD, the D2 receptor availability was reduced in the hippocampus: by 34% (P = 0.03) in the right hippocampus and by 14% (P = 0.78) in the left hippocampus as compared with controls. Multiple linear regression analysis showed that the BP in the right hippocampus had a significant positive association with verbal memory performance (Wechsler Memory Scale - Revised) (P = 0.001) and picture naming (the Boston Naming Test) (P = 0.002). Our findings suggest a role for temporal lobe D2 receptors in the memory and naming performance in AD, and suggest that studies to evaluate the efficiency of dopaminergic medication on patients with early AD might be warranted.

Evaluation of brain tumor metabolism with [11C]choline PET and 1H-MRS.

BACKGROUND: The signal of choline containing compounds (Cho) in proton magnetic resonance spectroscopy (1H-MRS) is elevated in brain tumors. [11C]choline uptake as assessed using positron emission tomography (PET) has also been suggested to be higher in brain tumors than in the normal brain. We examined whether quantitative analysis of choline accumulation and content using these two novel techniques would be helpful in non-invasive, preoperative evaluation of suspected brain tumors and tumor malignancy grade. METHODS: 12 patients with suspected brain tumor were studied using [11C]choline PET, gadolinium enhanced 3-D magnetic resonance imaging and 1H-MRS prior to diagnostic biopsy or resection. Eleven normal subjects served as control subjects for 1H-MRS. RESULTS: The concentrations of Cho and myoinositol (mI) were higher and the concentration of N-acetyl signal/group (NA) lower in brain tumors than in the corresponding regions of the normal brain. There were no significant differences in metabolite concentrations between low- and high-grade gliomas. In non-tumorous lesions Cho concentrations were lower and NA concentrations higher than in any of the gliomas. Enormously increased lipid peak differentiated lymphomas from all other lesions. The uptake of [11C]choline at PET did not differ between low- and high-grade gliomas. The association between Cho concentration determined in 1H-MRS and [11C]choline uptake measured with PET was not significant. CONCLUSION: Both 1H-MRS and [11C]choline PET can be used to estimate proliferative activity of human brain tumors. These methods seem to be helpful in differential diagnosis between lymphomas, non-tumorous lesions and gliomas but are not superior to histopathological methods in estimation of tumor malignancy grade.

Brain acetylcholinesterase activity in mild cognitive impairment and early Alzheimer's disease.

OBJECTIVE: Brain acetylcholinesterase activity was determined in healthy controls and in patients with mild cognitive impairment and early Alzheimer's disease. METHODS: A specific acetylcholinesterase tracer, [methyl-(11)C]N-methyl-piperidyl-4-acetate ([(11)C]MP4A), and a three dimensional PET system with magnetic resonance coregistration were used for imaging. RESULTS: There was a significant difference in the acetylcholinesterase activity in the hippocampus between the groups (p = 0.03), the mean (SD) acetylcholinesterase activity (k(3) values, min(-1)) being 0.114 (0.036) in controls, 0.098 (0.023) in mild cognitive impairment, and 0.085 (0.022) in Alzheimer's disease. The mini-mental state examination score showed no significant relation with acetylcholinesterase activity in any brain area in the combined mild cognitive impairment/Alzheimer group. CONCLUSIONS: Hippocampal acetylcholinesterase activity is only slightly reduced in mild cognitive impairment and early Alzheimer's disease and so the value of in vivo acetylcholinesterase measurements in detecting the early Alzheimer process is limited.

Severe somatization in women is associated with altered cerebral glucose metabolism.

BACKGROUND: Somatization is a clinical phenomenon characterized by multiple, medically unexplained somatic symptoms. The pathophysiology remains unknown. We aimed to test the hypothesis of a central nervous system dysfunction in the pathophysiology of this disorder. METHOD: We studied 10 female patients diagnosed as having somatization disorder or undifferentiated somatoform disorder with no current Axis I disorders according to DSM-IV. They were compared with 17 healthy female volunteers using brain [18F]-fluorodeoxyglucose-PET with MRI reference. RESULTS: The patients had lower cerebral metabolism rates of glucose (P<0.05) in both caudate nuclei, left putamen and right precentral gyrus compared with healthy volunteers. CONCLUSIONS: This is the first study to demonstrate changes in brain metabolism in somatizing women. The regional cerebral hypometabolism is probably associated with the pathophysiology of somatization.

Evaluation of the relationship between preoperative risk scores, postoperative and total length of stays and hospital costs in coronary bypass surgery.

OBJECTIVES: Several risk indices have been developed for the prediction of postoperative mortality and morbidity in coronary artery bypass operations, in which the risk scores are currently recorded as routine praxis. The aim of the present study was to determine whether the risk scores can be used to predict the hospital (LOS) and postoperative (POS) lengths of stay and total costs among coronary artery bypass graft (CABG) patients. METHODS: All first-time CABG patients (n=2104) treated at Helsinki University Central Hospital during 1997-1998 were preoperatively scored using the Cleveland Clinic preoperative model. A multivariate analysis was used to evaluate the effects of the risk scores on the LOS and POS and total costs. RESULTS: The mean preoperative risk score for the patients was 1.69. The increase in preoperative risk score was associated with an increase in the LOS (0.8 days by point), and POS (with 0.55 days by point). An age over 74 years increased the LOS by an extra day. The mean total cost for the CABG procedure was 8750 euros (SD 4430 euros). The costs increased as the risk score increased. Compared with the zero risk score, a score value of 2 was associated with a 1300 euros increase in total cost and a score value of over 6 was associated with an over 7000 euros cost increase. On average, the costs increased by 6980 euros (80%) for one major complication and by 935 euros (10%) in the elderly (>74 years of age). CONCLUSIONS: The results show that increasing risk scores were associated with longer postoperative hospital lengths of stay (POS and LOS) and with increased total costs. An age over 74 years appears to be an independent risk factor in increased POS, LOS and total cost. These results may help to estimate the impact of the preoperative risk profile on the resource requirement in CABG surgery.

Phenotype of a homozygous CADASIL patient in comparison to 9 age-matched heterozygous patients with the same R133C Notch3 mutation.

BACKGROUND AND PURPOSE: CADASIL is an autosomal dominant arteriopathy, characterized by multiple brain infarcts, cognitive decline, and finally dementia, which is caused by mutations in Notch3 gene encoding a Notch3 receptor protein. We describe the clinical, neuropsychological, imaging, genetic, and skin biopsy findings in a CADASIL patient homozygous for the C475T mutation resulting in R133C amino acid substitution, in comparison to 9 age-matched heterozygous patients with the same mutation. METHODS: The patients were examined clinically and neuropsychologically and with MRI and positron emission tomography for assessment of cerebral blood flow. The gene defect was analyzed by sequencing the products of polymerase chain reaction of exons 3 and 4 of the Notch3 gene. Dermal arteries were analyzed electron microscopically. RESULTS: The homozygous patient had his first-ever stroke at age 28 years. This is markedly earlier than the average, but the patient's heterozygous son had his first transient ischemic attack-like episode at the same age and another heterozygous patient had his first-ever stroke when only 2 years older. He was neuropsychologically more severely deteriorated than all but 1 of the heterozygous patients. These 2 patients had the most severe (confluent grade D) white matter MRI changes. Positron emission tomography showed markedly reduced cerebral blood flow. Skin biopsy revealed profuse deposits of granular osmiophilic material. The progression of disease in the homozygous case was, however, slower than in the most severely affected heterozygous patient. CONCLUSIONS: Our homozygous patient's phenotype is within the clinical spectrum of CADASIL, although at its severe end. Thus, CADASIL may follow the classic definition of a dominant disease, according to which the heterozygous and homozygous patients are clinically indistinguishable.

Insulin-like growth factor-binding protein-1 in cervical secretion as a predictor of preterm delivery.

BACKGROUND: The aim of the study was to evaluate whether the phosphorylated isoforms of insulin-like growth factor-binding protein-1 (IGFBP-1), a protein produced by the decidua, can be detected in cervical secretions of pregnant women with preterm uterine contractions, and whether their presence predicts an increased risk of preterm delivery. METHODS: A prospective analysis of sixty-three women who presented with preterm labor but intact fetal membranes at weeks 22-36+6 days of gestation at the Antenatal clinic at the Department of Obstetrics and Gynecology, Helsinki University Central Hospital. Phosphorylated IGFBP-1 (phIGFBP-1) was measured in cervical swab samples obtained at presentation, using an immunoenzymometric assay. The values > or =10 microg/L were considered as positive. In addition, 58 asymptomatic women at the same gestational stage were studied as controls. Multiple logistic regression was applied to control for confounding variables and to obtain adjusted odds ratios. RESULTS: The concentration of phIGFBP-1 in cervical samples ranged from undetectable to 95 microg/L. In 17 of the 63 (27%) women with preterm labor it was > or =10 microg/L. Seven of these 17 (41%) women with a positive phIGFBP-1 result delivered preterm, all before 35 weeks of gestation. Among the women with preterm labor and a negative phIGFBP-1 result, three of the 46 (7%) delivered before 37 weeks of gestation (adjusted OR 24, 95% CI 1.2-487), but all after 35 weeks of gestation. In the asymptomatic control population three out of 58 (5%) women had a positive cervical phIGFBP-1 test result but none delivered preterm. Among the controls with a negative cervical phIGFBP-1 test result (55 of 58, 95%), one woman delivered preterm (1 of 55, 2%). CONCLUSIONS: Pregnant women who are in preterm labor with intact fetal membranes and who have a positive phIGFBP-1 test result in cervical secretion have an increased risk of preterm delivery.

Vaginal clindamycin in preventing preterm birth and peripartal infections in asymptomatic women with bacterial vaginosis: a randomized, controlled trial.

OBJECTIVE: To determine whether treatment of bacterial vaginosis (BV) in early pregnancy decreases the risk of preterm delivery and peripartum infectious morbidity. METHODS: In this multicenter, randomized, double-masked, placebo-controlled intervention trial, screening for BV was performed by vaginal Gram stain obtained from 5432 healthy women with singleton pregnancies during the first antenatal clinic visit at 10--17 weeks' gestation. Bacterial vaginosis-positive women with no past history of preterm delivery were randomized to a single course of treatment with either 2% vaginal clindamycin cream or identical placebo cream for 7 days. Repeat Gram stains were taken 1 week after treatment and at 30--36 weeks' gestation. Preterm delivery was defined as spontaneous delivery before 37 gestational weeks. Peripartum infectious morbidity was defined as postpartum endometritis, postpartum sepsis, postcesarean wound infection, or episiotomy wound infection, necessitating antimicrobial therapy. According to the power analysis, 180 patients were needed for both treatment arms to show a three-fold difference in the rates of preterm births. RESULTS: The overall prevalence of BV was 10.4%. Of all BV-positive women, 375 (66%) were randomized to the treatment arms. The primary cure rate was 66% in the clindamycin group; in the placebo group, 34% spontaneously cleared BV (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.3, 2.8). The rate of preterm deliveries was 5% in the clindamycin group and 4% in the placebo group (OR 1.3, 95% CI 0.5, 3.5). The rate of peripartum infectious morbidity was 11% in the clindamycin group and 18% in the placebo group (OR 1.6, 95% CI 0.9, 2.8). Bacterial vaginosis recurred in 7% of women. The rate of preterm deliveries was 15% in this subgroup compared with 2% among women who remained BV negative (OR 9.3, 95% CI 1.6, 53.5). CONCLUSION: Vaginal clindamycin did not decrease the rate of preterm deliveries or peripartum infections, but recurrent or persistent BV increased the risk for these complications.