Effect of far infrared therapy on arteriovenous fistula maturation, survival and stenosis in hemodialysis patients, a randomized, controlled clinical trial: the FAITH on fistula trial.

BACKGROUND: An arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis treatment. After creation many of the AVFs will never mature or if functioning will need an intervention within 1 year due to an AVF stenosis. Studies investigating possible therapies that improves the AVF maturation and survival are scarce. Far infrared therapy (FIR) has shown promising results. In minor single centre and industry supported trials FIR has shown improved AVF maturation and survival. There is a need of a randomized multicentre controlled trial to examine the effect of FIR on the AVF maturation and survival and to explore the possible AVF protective mechanism induced by the FIR treatment. METHODS: This investigator initiated, randomized, controlled, open-labeled, multicenter clinical trial will examine the effect of FIR on AVF maturation in patients with a newly created AVF (incident) and AVF patency rate after 1 year of treatment in patients with an existing AVF (prevalent) compared to a control group. The intervention group will receive FIR to the skin above their AVF three times a week for 1 year. The control group will be observed without any treatment. The primary outcome for incident AVFs is the time from surgically creation of the AVF to successful cannulation. The primary outcome for the prevalent AVFs is the difference in number of AVFs without intervention and still functioning in the treatment and control group after 12 months. Furthermore, the acute changes in inflammatory and vasodilating factors during FIR will be explored. Arterial stiffness as a marker of long term AVF patency will also be examined. DISCUSSION: FIR is a promising new treatment modality that may potentially lead to improved AVF maturation and survival. This randomized controlled open-labelled trial will investigate the effect of FIR and its possible mechanisms. TRIAL REGISTRATION: Clinicaltrialsgov NCT04011072 (7th of July 2019).

Habitual dietary phosphorus intake and urinary excretion in chronic kidney disease patients: a 3-day observational study.

Hyperphosphatemia in chronic kidney disease (CKD) is associated with vascular calcification, cardiovascular morbidity and mortality. The aim of this study was to estimate the daily dietary phosphorus intake compared with recommendations in CKD patients and to evaluate the reproducibility of the 24-h urinary phosphorus excretion. Twenty CKD patients stage 3-4 from the outpatient clinic, collected 24-h urine and kept dietary records for 3 consecutive days. The mean daily phosphorus intake was 1367±499, 1642±815 and 1426±706 mg/day, respectively (P=0.57). The mean urinary phosphorus excretion was 914±465, 954±414 and 994±479 mg/day, respectively (P=0.21). In this population of CKD patients stage 3-4 the daily phosphorus intake was above the recommended. Twenty-four-hour urinary phosphorus excretion was reproducible and the data indicate that a single 24-h urine collection is sufficient to estimate the individual phosphorus excretion.

"Real-World" use of cinacalcet for managing SHPT in different European countries: analysis of data from the ECHO observational study.

AIMS: The pan-European ECHO observational study evaluated cinacalcet in adult dialysis patients with secondary hyperparathyroidism (SHPT) in "real-world" clinical practice. A sub-analysis compared data for 7 European countries/country clusters: Austria, CEE (Czech Republic and Slovakia), France, Italy, Netherlands, Nordics (Denmark, Finland, Norway, and Sweden), and the UK/Ireland. METHODS: Data on serum intact parathyroid hormone (iPTH), phosphorous, calcium, as well as the usage of cinacalcet, active vitamin D analogues and phosphate binders were compared. RESULTS: 1,865 patients (mean age 58 years) were enrolled: median baseline iPTH levels ranged from 605 pg/ml in Austria to 954 pg/ml in the UK/Ireland. After ~1 year of cinacalcet, median iPTH reductions from baseline ranged from 38% in the UK/Ireland to 58% in the Netherlands. The proportion of patients achieving NKF/K-DOQITM iPTH targets (150 - 300 pg/ml) at Month 12 ranged from 14% in the UK/Ireland to 40% in CEE. In general, use of sevelamer decreased, while use of calcium-based phosphate binders increased, during cinacalcet treatment. Vitamin D changes were more variable. CONCLUSION: The iPTH level at which cinacalcet is initiated in clinical practice differs considerably among different countries: where cinacalcet was started at a lower iPTH level this resulted in better achievement of serum iPTH targets.

Harnessing stakeholder perspectives to improve the care of osteoporosis after a fracture.

UNLABELLED: This study used in-depth interviews and focus groups to evaluate osteoporosis care after a fracture. Patients (eligible women aged 67 who sustained a clinical fracture(s)), clinicians, and staff stated that an outreach program facilitated osteoporosis care management, but more-tailored education and support and increased participation of orthopedic specialists appear necessary. INTRODUCTION: Osteoporosis treatment reduces fracture risk, but screening and treatment are underutilized, even after a fracture has occurred. This study evaluated key stakeholder perspectives about the care of osteoporosis after a fracture. METHODS: Participants were from a nonprofit health maintenance organization in the United States: eligible women members aged 67 or older who sustained a clinical fracture(s) (n = 10), quality and other health care managers (n = 20), primary care providers (n = 9), and orthopedic clinicians and staff (n = 28); total n = 67. In-depth interviews and focus groups elicited participant perspectives on an outreach program to patients and clinicians and other facilitators and barriers to care. Interviews and focus group sessions were transcribed and content-analyzed. RESULTS: Patients, clinicians, and staff stated that outreach facilitated osteoporosis care management, but important patient barriers remained. Patient knowledge gaps and fatalism were common. Providers stated that management needed to begin earlier, and longer-term patient support was necessary to address adherence. Orthopedic clinicians and staff expressed lack of confidence in their osteoporosis management but willingness to encourage treatment. CONCLUSIONS: Although an outreach program assisted with the management of osteoporosis after a fracture, more-tailored education and support and increased participation of orthopedic specialists appear necessary to maximize osteoporosis management.

Pegvisomant therapy in pituitary gigantism: successful treatment in a 12-year-old girl.

OBJECTIVE: The use of a growth hormone (GH) receptor antagonist, pegvisomant has shown great promise in adults with acromegaly, but experience in paediatric patients is lacking. We aimed to describe the results of pegvisomant therapy in a 12-year-old girl with an aggressive GH-secreting pituitary tumour. DESIGN: To evaluate the ability of pegvisomant therapy to control the effects of peripheral GH excess in a case of pituitary gigantism. METHODS: Pegvisomant was introduced at 10 mg/day, given subcutaneously, and gradually increased to 20 mg/day until serum IGF-I was normal for age. RESULTS: A large pituitary adenoma with suprasellar extension was diagnosed in a 12-year-old girl with progressive tall stature (178 cm), GH hypersecretion without suppression during oral glucose loading (nadir serum GH, 90 mU/l), high serum IGF-I and serum prolactin levels. Surgical extirpation was not possible because tumour tissue was fibrous and adherent to the optical nerves. Histological examination showed a mixed GH- and prolactin-secreting adenoma with lymphocytic infiltration of B and T cells. Treatment with a dopamine agonist, cabergoline, normalized serum prolactin, but GH secretion was resistant to both somatostatin analogue, octreotide and cabergoline. Radiation followed by pegvisomant therapy titrated up in dose to 20 mg/day led to a marked reduction in GH secretion and normalization of IGF-I, and to growth arrest and improvement of well-being. CONCLUSIONS: We suggest that treatment in pituitary gigantism with pegvisomant is safe and may normalize IGF-I levels and effectively stop growing.

Cushing's disease in childhood as the first manifestation of multiple endocrine neoplasia syndrome type 1.

OBJECTIVE: To describe three cases of Cushing's disease in children with multiple endocrine neoplasia type 1 (MEN1), as clinical manifestations of MEN1 are very rare in childhood. DESIGN AND METHODS: A retrospective review of three cases of Cushing's disease diagnosed between 1997 and 1999. Genetic screening for MEN1 gene mutation was performed in each patient. RESULTS: An ACTH-secreting microadenoma was diagnosed in three children, aged 11-13 years, presenting with growth retardation and weight gain over a period of 3-4 years. All patients had successful transsphenoidal adenomectomies. Primary hyperparathyroidism was subsequently diagnosed in two of the patients, and in the monozygotic twin of one of the patients. A new mutation in the MEN1 gene (Tyr351His) was identified in two of the patients and the affected members of their families. In the third patient a de novo MEN1 gene mutation (Leu444Pro) was found. CONCLUSIONS: MEN1 has to be considered in all children with tumours of the pituitary gland, and in those presenting with primary hyperparathyroidism. The children and their families should be advised to seek genetic counselling. We suggest that careful growth records be kept for children at risk of developing inherited MEN1 and, in the event of a decelerating growth rate, further diagnostic evaluation be undertaken with regards to ACTH-secreting pituitary tumours.

Neonatal hypoglycaemia and withdrawal symptoms after exposure in utero to valproate.

AIMS: To define, in a prospective study, the risk of hypoglycaemia-defined as blood glucose concentration < 1.8 mmol/l-in term infants exposed in utero to valproate and to describe the withdrawal symptoms. METHODS: Twenty epileptic women were treated with valproate only during pregnancy and two were treated with valproate and carbamazepine. In the first trimester, the daily median dose of valproate was 1.0 g (range 0.3-4.2) and in the third trimester 1.2 g (range 0.3-4.8). RESULTS: Thirteen of the 22 infants became hypoglycaemic. One infant had eight episodes of hypoglycaemia, one had three episodes, two had two episodes, and nine had one episode each. The lowest blood glucose concentration was 1.0 mmol/l. All episodes were asymptomatic. The maternal mean plasma concentration of total valproate during the third trimester correlated negatively with blood glucose concentration one hour after delivery (p < 0.0003) and with the development of hypoglycaemia (p < 0.0001). There was no evidence for hyperinsulinaemia as the cause of hypoglycaemia. Ten infants developed withdrawal symptoms, which correlated positively with the mean dose of valproate in the third trimester and the concentration of the free fraction of valproate in maternal plasma at delivery (p < 0.02). CONCLUSIONS: Infants exposed to valproate in utero had a significantly elevated risk of hypoglycaemia, and withdrawal symptoms were often observed.

[Granulosa cell tumors in children]. / Granulosacelletumorer hos børn.

Juvenile granulosa cell tumours (JGCT) are rare. They may develop in ovarian or testicular tissue. In childhood a special histological type called juvenile granulosa cell tumour (JGCT) is seen. Four cases are described: Congenital JGCT in a child with sex chromosomal abnormity (45 XO/46 XdicYq) and tumour arising from immature testicular tissue, JGCT in the testis of a four month old boy, JGCT associated with a hypothalmic hamartoma in a 18 month-old girl, and JGCT in an eight year-old girl. In all cases the tumours were benign.

Bone mineral density and biochemical markers of bone turnover in patients with predialysis chronic renal failure.

BACKGROUND: Metabolic bone disease might commence early in the course of renal failure. This study therefore examined the frequency and severity of the skeletal changes in predialysis chronic renal failure by measurements of bone mineral density (BMD), biochemical markers of bone turnover (osteocalcin, bone-specific alkaline phosphatase, carboxy terminal propeptide of type I collagen, and carboxy-terminal telopeptide of type I collagen), parathyroid hormone (PTH), ionized calcium (Ca++), phosphate (P), and vitamin D metabolites. METHODS: The study was performed in 113 patients (male/female: 82/31) with chronic renal diseases [mean glomerular filtration rate (GFR) of 37 ml/min] and in 89 matched, normal control subjects. RESULTS: The patients had significantly (P<0.05) reduced BMD in the spine (-6.3%), the femur (-12.1%), the forearm (-5.7%), and the total body (-4.2%) as compared with the control subjects. Dividing the patients into quartiles according to GFR revealed that BMD decreased with the gradual decline in renal function at all the measured skeletal sites, but was most pronounced in the femur: 0.63+/-0.03, 0.74+/-0.02, 0.77+/-0.02, and 0.82+/-0.03 g/cm2 in each quartile from lowest to highest GFR compared with 0.82+/-0.02 g/cm2 in the control group (P<0.0001). All of the measured bone markers showed increasing plasma levels with the more advanced stages of renal failure. Serum PTH and serum P levels increased, whereas serum Ca++ and 1,25-dihydroxyvitamin D decreased. BMD Z-scores of the femur and of the forearm correlated to the biochemical markers and to PTH (P<0.05 to P<0.0001). The biochemical markers all showed strong correlations to PTH, also when corrected for the effect of the decline in GFR (r = 0.40 to 0.92, P<0.01 to P< 0.0001). CONCLUSION: Skeletal changes are initiated at an early stage of chronic renal failure, as estimated from reduced BMD and elevated levels of PTH and from the biochemical markers of both bone formation and bone resorption.

Impact of peripheral neuropathy on bone density in patients with type 1 diabetes.

OBJECTIVE: To investigate whether peripheral neuropathy (PN), as part of the microangiopathic complex, affects bone mineral density (BMD) of the peripheral or the axial skeleton in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: Three study groups were examined. Group 1 comprised 21 males with type 1 diabetes and severe PN with a mean (range) duration of diabetes of 28 (9-59) years and an HbA1c of 8.2% (6.3-10.4). Group 2 comprised 21 male type 1 diabetic patients with absent or mild PN matched to patients of group 1 regarding age, weight, and duration of diabetes. Group 3 comprised 21 control subjects. BMD was measured by dual-energy x-ray absorptiometry (DEXA) and by quantitative ultrasound of the calcaneus. PN was determined by biothesiometry. Levels of physical activity were assessed through guided questionnaires. RESULTS: In group 1, BMD was significantly reduced at all measured sites, compared with an expected Z score of 0 (spine, -1.01 +/- 0.34; femur, -0.94 +/- 0.25; forearm, -1.10 +/- 0.36). To a lesser extent, but still significantly, group 2 also showed reduced BMD values (spine, -0.60 +/- 0.26; femur, -0.55 +/- 0.25; forearm, -1.05 +/- 0.36), whereas group 3 had normal BMD values (-0.23 +/- 0.25, -0.10 +/- 0.21, -0.07 +/- 0.25, respectively). Group 1 had lower mean BMD levels than group 2 and group 3 at all measured sites, but a significant difference was found only between groups 1 and 3 at the site of the femur (analysis of variance, P < 0.05). Broadband ultrasound attenuation (BUA) of the calcaneus was significantly reduced in group 1 compared with groups 2 and 3 (108 +/- 3 vs. 115 +/- 2 and 115 +/- 2). Significant correlations between all DEXA measurements and BUA were demonstrated in both groups 1 and 2 (r values between 0.54 and 0.75). No significant differences in physical activity levels or body composition were demonstrated between the two patient groups. CONCLUSIONS: The present results suggest that in patients with type 1 diabetes, PN may be an independent risk factor for reduced BMD in the affected limbs as well as in the skeleton in general.

Gender, age, and body weight are the major predictive factors for bone mineral density in Crohn's disease: a case-control cross-sectional study of 113 patients.

OBJECTIVE: We conducted this study to assess bone mineral density and to evaluate conceivable predictive factors for bone loss in patients with Crohn's disease. METHODS: One hundred-thirteen patients with Crohn's disease and 113 healthy subjects, individually matched for gender, age, and body weight were investigated. The group consisted of 68 women and 45 men. The median duration of Crohn's disease was 6 yr. Two-thirds of the patients had been subjected to intestinal resection. Seventy-seven percent had at some time been treated with corticosteroids. Bone mineral density in the lumbar spine, the hip, and the total body skeleton was measured by dual-energy X-ray absorptiometry (DEXA). RESULTS: In patients with Crohn's disease bone mineral density was not different from that of healthy controls except for a regional decrease in bone mineral density of the hip in female patients. The strongest predictors of bone mineral density were gender, age, and body weight. Corticosteroid use was only a weak predictor of diminished bone density. Duration of disease and intestinal resection had no predictive value for bone mineral density. CONCLUSIONS: Gender, age, and body weight are the major determinants of bone mineral density in patients with Crohn's disease. As in healthy individuals, the combined effect of these factors account for up to 50% of the variability in bone mineral density.

Regulators of calcium homeostasis and bone mineral density in patients with Crohn's disease.

BACKGROUND: Several papers have reported on vitamin D, parathyroid hormone (PTH), and other regulators of calcium metabolism in patients with Crohn's disease, but results have been conflicting. Bone mineral density (BMD) has been found to be reduced in several papers. A recent study from our laboratory suggested that the expected reduction in BMD disappears when the patients are compared with sex-, age-, and weight-matched healthy controls. The relationship between BMD and regulators of calcium homeostasis is not well established in patients with Crohn's disease. METHODS: BMD and biochemical regulators of calcium metabolism were measured in 115 unselected patients with Crohn's disease, most of whom were in remission. RESULTS: Vitamin D deficiency (25-OHD < or = 10 pg/ml) was present in 44% of patients. Secondary hyperparathyroidism was present in 2% of unoperated patients and in 18% of patients subjected to bowel operations. CONCLUSIONS: 1) Vitamin D deficiency is common in patients with Crohn's disease even when the disease is in remission and regardless of the location of the disease. 2) Secondary hyperparathyroidism is most frequently seen in patients who have undergone intestinal resection(s). 3) PTH correlates with BMD in a large group of unselected patients with Crohn's disease; 25-OHD only correlates with BMD of the forearm.

High bone turnover is associated with low bone mass and spinal fracture in postmenopausal women.

A group of 366 healthy, white postmenopausal women, aged 50-81 years, mean age 66 years, were selected from the screened population of Scandinavians who were part of a multicenter study of the efficacy of tiludronate, a new bisphosphonate, in established postmenopausal osteoporosis. Eighty-eight women had a lumbar spine bone mineral density (BMD) above 0.860 g/cm2, and 278 women had a BMD below 0.860 g/cm2. Spinal fracture was diagnosed from lateral spine X-ray studies and defined as at least 20% height reduction (wedge, compression, or endplate fracture) in at least one vertebra (T4-L4). Bone resorption was assessed by measurement of the urinary excretion of type I collagen degradation products by the CrossLaps enzyme-linked immunoassay (ELISA). Bone formation was assessed by ELISA measurement of the N-terminal-midfragment as well as the intact serum osteocalcin (OCN-MID), thus omitting the influence of the instability of osteocalcin caused by the labile 6 amino acid C-terminal sequence. The women were divided into groups with high or low bone turnover according to the concentrations of urinary Cross-Laps or OCN-MID. Women in the quartiles with the highest concentrations of CrossLaps [519 +/- 119 micrograms/mmol (SD)] or OCN-MID [44.6 +/- 7.5 ng/ml (SD)] had 10-16% lower spinal BMD compared with women in the lowest quartiles (CrossLaps 170 +/- 48 micrograms/mmol (SD), and OCN-MID [22.1 +/- 3.0 ng/ml (SD)] (P < 0.0004). The prevalences of spinal fracture were 25 to 29% in the lowest quartiles, whereas the prevalences in the highest quartiles were almost double-53-54% (P < 0.006). If the women were subgrouped according to spinal BMD and prevalence of spinal fracture, corresponding results were found. Women with a BMD less than 0.860 g/cm2, without or with spinal fracture (n = 136 and n = 142), had 36-43% higher concentration of Cross-Laps (P = 0.0001) and 11-15% higher concentration of OCN-MID (P < 0.02), as compared with women with a BMD above 0.860 g/cm2 and no spinal fracture (n = 84). In conclusion, the results indicate a strong association among high bone turnover, low bone mass, and prevalence of spinal fracture, which supports the theory that high bone turnover is a risk factor for spinal fracture and osteoporosis.

Capillary plasma neutrophil elastase alpha-1-proteinase inhibitor as infection parameter in neonates.

Raised plasma neutrophil elastase has been reported to be an early and effective marker of infection in neonates. In order to assess the feasibility of implementing a rapid assay on capillary plasma, repeated heel prick samples were taken in a series of 79 neonates with clinically suspected bacterial infection, comparing the elastase response with C-reactive protein (CRP) and with the band:mature neutrophil ratio. Rises in elastase were in agreement with rises in CRP, but were more frequently manifest at onset of symptoms, showing elastase to be a more rapid marker of infection as previously described. However, 23% of elastase measurements either failed due to haemolysis or coagulation or yielded inexplicably high values. Comparison of simultaneous bilateral heel prick values confirmed unacceptable variation, unlike comparison of paired venous samples or venous and capillary samples from adults, indicating that capillary blood sampling in neonates produces an unpredictable release of neutrophil elastase. Thus, in newborn infants samples for determination of elastase should be taken by venous punctures or from indwelling catheters.

Fetal akinesia-hypokinesia deformation sequence (FADS) in 2 siblings with congenital myotonic dystrophy.

Two premature siblings described herein had clinical features comparable to the fetal akinesia-hypokinesia deformation sequence (Pena-Shokeir syndrome) with polyhydramnios, intrauterine growth retardation, pulmonary hypoplasia, short umbilical cord and lethality. Autopsy revealed no thoracal or abdominal viscera anomalies and examination of the brain, spinal cord and peripheral nerves did not disclose any pathological changes. Light microscopy, immunohistochemistry and electron microscopy of skeletal muscles demonstrated immature muscles with some fibril disorganisation and abnormal immunoreactivity for actin and desmin. Subsequent molecular genetic analysis revealed a maternal diagnosis of myotonic dystrophy. The retarded growth and maturation of skeletal muscle observed in the presented cases correspond with previous findings in neonatal myotonic dystrophy. A well-defined myopathy can thus result in the fetal akinesia-hypokinesia deformation sequence.

Cerebral irradiation causes blunted pubertal growth in girls treated for acute leukemia.

The improved treatment of childhood leukemia is a major achievement. The late effects of the treatment need further investigation. Growth inhibition has been demonstrated in earlier studies. Growth and the timing of puberty were studied in 179 girls who had been treated for acute lymphoblastic leukemia (ALL) in Denmark, Finland, Norway, and Sweden. The patients were divided into two groups according to mode of CNS prophylaxis: with or without cerebral irradiation. Longitudinal analysis of 103 patients showed no difference in prepubertal growth in irradiated and nonirradiated girls. Growth during puberty was normal in girls without irradiation and below normal in irradiated girls. There was no difference in growth between girls after 24 Gy or 20 Gy of cerebral irradiation. Irradiated girls had a final height which was one SD less than expected before puberty and menarche occurred one year earlier than in the nonirradiated girls. Prophylactic cerebral irradiation is the most important factor for subnormal growth after treatment for ALL. There is no short-term influence on growth but the effects of irradiation become apparent several years after therapy when girls enter puberty somewhat early and have a subnormal pubertal growth. Growth and growth hormone (GH) levels should be evaluated several years after CNS irradiation, and treatment with GH and/or luteinizing hormone releasing hormone (LHRH) analogues may be considered.

[Rat-bite--an infant bitten by a rat]. / Rottebid--spaedbarn bidt af rotte.

Three days after a rat-bite a two-month-old girl developed clinical symptoms of Streptobacillus moniliformis infection, called rat-bite fever. She became seriously ill, but responded well to treatment with benzylpencillin. In the light of our case and previous publications, we recommend prophylactic penicillin to be given to infants after rat-bites.

Intratubular germ cell neoplasia in an infantile testis with immature teratoma.

A case of intratubular germ cell neoplasia adjacent to an immature teratoma is described in an 8-month-old boy with normally descended testes. The pattern of intratubular germ cell neoplasia in the infantile testis appeared different from that in the adult, but the abnormal germ cells were morphologically and immunohistochemically similar. In the few previous reports, which have investigated infantile testicular tissue for the presence of intratubular germ cell neoplasia adjacent to germ cell tumours, intratubular germ cell neoplasia in conjunction with a yolk sac tumour and mature teratoma have not been found, and cases with immature teratoma have not been reported. The presence of intratubular germ cell neoplasia in conjunction with immature teratoma and its apparent absence in conjunction with the mature form and with yolk sac tumour may indicate difference in tumour development. Whether there is a true difference in the occurrence of intratubular germ cell neoplasia in the infantile testis according to the various types of germ cell tumours remains, however, to be proven by investigations of more cases.

[Congenital stomatocytosis with hemolytic anemia--with abnormal cation permeability and defective membrane proteins]. / Medfødt stomatocytose med haemolytisk anaemi--med abnorm kationpermeabilitet og defekte membranproteiner.

A case of hereditary stomatocytosis with haemolytic anaemia in a nine year-old girl is presented. This rare syndrome is associated with increased permeability for monovalent cations across the erythrocyte membrane leading to high intracellular sodium (72 mmol/l erythrocytes) and low potassium (32 mmol/l erythrocytes) accompanied by an increased water content. In our patient the passive Na+ and K+ flux were increased to approximately 20 times normal with a compensatory maximal activation of the normal Na, K transport. The cation permeability defect was partly corrected in vitro by a bifunctional imidoester, dimethyl suberimidate. Electrophoresis of solubilizer membrane proteins revealed changes in the protein band pattern with reduction of band 7, as reported previously, and increase in the band 4.1a/4.1b ratio and increased band 4.8.