Interactive video retrieval evaluation at a distance: comparing sixteen interactive video search systems in a remote setting at the 10th Video Browser Showdown.

The Video Browser Showdown addresses difficult video search challenges through an annual interactive evaluation campaign attracting research teams focusing on interactive video retrieval. The campaign aims to provide insights into the performance of participating interactive video retrieval systems, tested by selected search tasks on large video collections. For the first time in its ten year history, the Video Browser Showdown 2021 was organized in a fully remote setting and hosted a record number of sixteen scoring systems. In this paper, we describe the competition setting, tasks and results and give an overview of state-of-the-art methods used by the competing systems. By looking at query result logs provided by ten systems, we analyze differences in retrieval model performances and browsing times before a correct submission. Through advances in data gathering methodology and tools, we provide a comprehensive analysis of ad-hoc video search tasks, discuss results, task design and methodological challenges. We highlight that almost all top performing systems utilize some sort of joint embedding for text-image retrieval and enable specification of temporal context in queries for known-item search. Whereas a combination of these techniques drive the currently top performing systems, we identify several future challenges for interactive video search engines and the Video Browser Showdown competition itself.

MAP2K1-Mutated Melanocytic Neoplasms With a SPARK-Like Morphology.

ABSTRACT: Specific alterations involving MAPK genes (MAP3K8 fusions, MAP3K3 fusions) have been recently detected in a subgroup of spitzoid neoplasms that seem to constitute a distinctive clinicopathologic group, occur mostly in younger patients (median age 18 years) and present with atypical histologic features associated with frequent homozygous deletion of CDKN2A, qualifying a high proportion of them as Spitz melanoma (malignant Spitz tumor). Apart from lesions with spitzoid morphology harboring MAP3K8 or MAP3K3 fusion, a single case with MAP2K1 deletion has been identified. The authors report herein 4 melanocytic lesions with a MAP2K1 mutation, all showing similar microscopic appearances, including spitzoid cytology and dysplastic architectural features, resembling so-called SPARK nevus, suggesting that these lesions may represent another distinctive group.

Pre- and postnatal growth failure with microcephaly due to two novel heterozygous IGF1R mutations and response to growth hormone treatment.

AIM: To explore the phenotype and response to growth hormone in patients with heterozygous mutations in the insulin-like growth factor I receptor gene (IGF1R). METHODS: Children with short stature, microcephaly, born SGA combined with biochemical sign of IGF-I insensitivity were analysed for IGF1R mutations or deletions using Sanger sequencing and Multiple ligation-dependent probe amplification analysis. RESULTS: In two families, a novel heterozygous non-synonymous missense IGF1R variant was identified. In family 1, c.3364G > T, p.(Gly1122Cys) was found in the proband and co-segregated perfectly with the phenotype in three generations. In family 2, a de novo variant c.3530G > A, p.(Arg1177His) was detected. Both variants were rare, not present in the GnomAD database. Three individuals carrying IGF1R mutations have received rhGH treatment. The average gain in height SDS during treatment was 0.42 (range: 0.26-0.60) and 0.64 (range: 0.32-0.86) after 1 and 2 years of treatment, respectively. CONCLUSION: Our study presents two heterozygous IGF1R mutations causing pre- and postnatal growth failure and microcephaly and also indicates that individuals with heterozygous IGF1R mutations can respond to rhGH treatment. The findings highlight that sequencing of the IGF1R should be considered in children with microcephaly and short stature due to pre- and postnatal growth failure.

An Increased Diagnostic Sensitivity of Truncated GAD65 Autoantibodies in Type 1 Diabetes May Be Related to HLA-DQ8.

N-terminally truncated (96-585) GAD65 (tGAD65) autoantibodies may better delineate type 1 diabetes than full-length GAD65 (fGAD65) autoantibodies. We aimed to compare the diagnostic sensitivity and specificity between fGAD65 and tGAD65 autoantibodies for type 1 diabetes in relation to HLA-DQ. Sera from children and adolescents with newly diagnosed type 1 diabetes (n = 654) and healthy control subjects (n = 605) were analyzed in radiobinding assays for fGAD65 (fGADA), tGAD65 (tGADA), and commercial 125I-GAD65 (RSRGADA) autoantibodies. The diagnostic sensitivity and specificity in the receiver operating characteristic curve did not differ between fGADA and tGADA. At the optimal cutoff, the diagnostic sensitivity for fGADA was lower than tGADA at similar diagnostic specificities. In 619 patients, 64% were positive for RSRGADA compared with 68% for fGADA and 74% for tGADA. Using non-DQ2/non-DQ8 patients as reference, the risk of being diagnosed with fGADA and tGADA was increased in patients with DQ2/2 and DQ2/8. Notably, logistic regression analysis suggested that DQ8/8 patients had an increased risk to be diagnosed with tGADA (P = 0.003) compared with fGADA (P = 0.09). tGADA had a higher diagnostic sensitivity for type 1 diabetes than both fGADA and RSRGADA. As DQ8/8 patients represent 10-11% of patients with newly diagnosed type 1 diabetes <18 years of age, tGADA analysis should prove useful for disease classification.

Hyperglycemia in Acutely Ill Non-diabetic Children in the Emergency Rooms of 2 Tertiary Hospitals in Lagos, Nigeria.

OBJECTIVES: The study aimed to determine the prevalence of hyperglycemia in sick children admitted into the emergency rooms and to investigate its relationship with adverse outcomes. METHODS: A prospective study involving 2 tertiary hospitals in Lagos. Study subjects included all children aged beyond 1 month. An Accu-Chek Active glucometer was used for the bedside blood glucose determination. Hyperglycemia was defined as blood glucose greater than 7.8 mmol/L. RESULTS: A total of 1045 patients were recruited with hyperglycemia being recorded in 135 patients (prevalence rate of 12.9%). Mean age of the hyperglycemic patients was 29.0 ± 31.23 months. Prevalence rates of hyperglycemia among the leading diagnoses were 17.4% in acute respiratory tract infections, 11% in malaria, 15.3% in septicemia, 14.9% in gastroenteritis, and 18.2% in burns. Other conditions include sickle cell anemia, meningitis, and malnutrition. Mortality rate was significantly higher overall in hyperglycemic compared with the normoglycemic patients (15.4% vs 8.0%, P = 0.011). With regard to specific diagnoses, significantly higher mortality rates were recorded in hyperglycemic patients with acute respiratory tract infections (28% vs 8%, P = 0.011) and malaria (21.4% vs 5.0%, P = 0.006) than in their normoglycemic counterparts. CONCLUSIONS: Hyperglycemia is common in ill children admitted to the emergency rooms and is associated with 2 to 4 times higher mortality in common childhood diseases encountered. Blood glucose determination is important in all acutely ill children at presentation. The practice of empirical administration of intravenous glucose in some resource-constrained facilities where blood glucose testing facilities are not readily available should be discouraged.

First-borns have greater BMI and are more likely to be overweight or obese: a study of sibling pairs among 26,812 Swedish women.

BACKGROUND: A number of large studies have shown phenotypic differences between first-borns and later-borns among adult men. In this study, we aimed to assess whether birth order was associated with height and BMI in a large cohort of Swedish women. METHODS: Information was obtained from antenatal clinic records from the Swedish National Birth Register over 20 years (1991-2009). Maternal anthropometric data early in pregnancy (at approximately 10-12 weeks of gestation) were analysed on 13,406 pairs of sisters who were either first-born or second-born (n=26,812). RESULTS: Early in pregnancy, first-born women were of BMI that was 0.57 kg/m(2) (2.4%) greater than their second-born sisters (p<0.0001). In addition, first-borns had greater odds of being overweight (OR 1.29; p<0.0001) or obese (OR 1.40; p<0.0001) than second-borns. First-borns were also negligibly taller (+1.2 mm) than their second-born sisters. Of note, there was a considerable increase in BMI over the 18-year period covered by this study, with an increment of 0.11 kg/m(2) per year (p<0.0001). CONCLUSIONS: Our study corroborates other large studies on men, and the steady reduction in family size may contribute to the observed increase in adult BMI worldwide.

Genetic screening in sudden cardiac death in the young can save future lives.

BACKGROUND: Autopsy of sudden cardiac death (SCD) in the young shows a structurally and histologically normal heart in about one third of cases. Sudden death in these cases is believed to be attributed in a high percentage to inherited arrhythmogenic diseases. The purpose of this study was to investigate the value of performing post-mortem genetic analysis for autopsy-negative sudden unexplained death (SUD) in 1 to 35 year olds. METHODS AND RESULTS: From January 2009 to December 2011, samples from 15 cases suffering SUD were referred to the Department of Clinical Genetics, Umeå University Hospital, Sweden, for molecular genetic evaluation. PCR and bidirectional Sanger sequencing of genes important for long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome type 1 (BrS1), and catecholaminergic polymorphic ventricular tachycardia (CPVT) (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, and RYR2) was performed. Multiplex ligation-dependent probe amplification (MLPA) was used to detect large deletions or duplications in the LQTS genes. Six pathogenic sequence variants (four LQTS and two CPVT) were discovered in 15 SUD cases (40%). Ten first-degree family members were found to be mutation carriers (seven LQTS and three CPVT). CONCLUSION: Cardiac ion channel genetic testing in autopsy-negative sudden death victims has a high diagnostic yield, with identification of the disease in 40 of families. First-degree family members should be offered predictive testing, clinical evaluation, and treatment with the ultimate goal to prevent sudden death.

Growth hormone (GH) dose-dependent IGF-I response relates to pubertal height gain.

BACKGROUND: Responsiveness to GH treatment can be estimated by both growth and ∆IGF-I. The primary aim of the present study was to investigate if mimicking the physiological increase during puberty in GH secretion, by using a higher GH dose could lead to pubertal IGFs in short children with low GH secretion. The secondary aim was to explore the relationship between IGF-I, IGFBP-3 and the IGF-I/IGFBP-3 ratio and gain in height. METHODS: A multicentre, randomized, clinical trial (TRN88-177) in 104 children (90 boys), who had received GH 33 µg/kg/day during at least 1 prepubertal year. They were followed from GH start to adult height (mean, 7.5 years; range, 4.6-10.7). At onset of puberty, children were randomized into three groups, to receive 67 µg/kg/day (GH(67)) given once (GH(67x1); n = 30) or divided into two daily injection (GH(33x2); n = 36), or to remain on a single 33 µg/kg/day dose (GH(33x1); n = 38). The outcome measures were change and obtained mean on-treatment IGF-I(SDS), IGFBP3(SDS) and IGF-I/IGFBP3 ratio(SDS) during prepuberty and puberty. These variables were assessed in relation to prepubertal, pubertal and total gain in heightSDS. RESULTS: Mean prepubertal increases 1 year after GH start were: 2.1 IGF-I(SDS), 0.6 IGFBP3(SDS) and 1.5 IGF-I/IGFBP3ratio(SDS). A significant positive correlation was found between prepubertal ∆IGFs and both prepubertal and total gain in height(SDS). During puberty changes in IGFs were GH dose-dependent: mean pubertal level of IGF-I(SDS) was higher in GH(67) vs GH(33) (p = 0.031). First year pubertal ∆IGF-I(SDS) was significantly higher in the GH(67)vs GH(33) group (0.5 vs -0.1, respectively, p = 0.007), as well as ∆IGF-I(SDS) to the pubertal mean level (0.2 vs -0.2, p = 0.028). In multivariate analyses, the prepubertal increase in '∆IGF-I(SDS) from GH start' and the 'GH dose-dependent pubertal ∆IGF-I(SDS)' were the most important variables for explaining variation in prepubertal (21 %), pubertal (26 %) and total (28 %) gain in height(SDS). TRIAL REGISTRATION: TRN 88-177, not applicable 1988. CONCLUSION: The dose-dependent change in IGFs was related to a dose-dependent pubertal gain in height(SDS). The attempt to mimic normal physiology by giving a higher GH dose during puberty was associated with both an increase in IGF-I and a dose-dependent gain in height(SDS).

Country-based reference values and international comparisons of clitoral size in healthy Nigerian newborn infants.

AIM: Clitoral size references are useful for diagnosing genital abnormalities. Despite the fact that examining the genitalia is an important aspect of newborn evaluation, few studies have been carried out to determine normal clitoral size in newborn infants. The aim of this study was to establish reference values for clitoral size in Nigerian newborn girls and to compare them with references from other ethnic populations. METHODS: A total of 244 healthy newborn girls delivered at 28-43 weeks gestation were enrolled in the study, and clitoral lengths and widths were measured at <72 hours. RESULTS: The mean clitoral length was 7.7 mm with a standard deviation of ±1.37 mm, while the mean clitoral width was 4.40 ± 0.89 mm. The clitoral length was significantly longer than those reported for Caucasian (4.00 ± 1.24 mm), Korean (3.82 ± 1.47), Turkish (4.93 ± 1.61) and Japanese (4.30 ± 1.10) babies. CONCLUSION: The present results make it possible to evaluate clitoral size in Nigerian newborn baby girls in an objective way, to identify genital abnormalities and endocrine disorders. Based on this study, a clitoral length of more than 10 mm would be considered clitoromegaly in a newborn girl in Nigeria.

Adapted ECHO-7 virus Rigvir immunotherapy (oncolytic virotherapy) prolongs survival in melanoma patients after surgical excision of the tumour in a retrospective study.

An oncolytic, nonpathogenic ECHO-7 virus adapted for melanoma that has not been genetically modified (Rigvir) is approved and registered for virotherapy, an active and specific immunotherapy, in Latvia since 2004. The present retrospective study was carried out to determine the effectiveness of Rigvir in substage IB, IIA, IIB and IIC melanoma patients on time to progression and overall survival. White patients (N=79) who had undergone surgical excision of the primary melanoma tumour were included in this study. All patients were free from disease after surgery and classified into substages IB, IIA, IIB and IIC. Circulating levels of clinical chemistry parameters were recorded. Survival was analysed by Cox regression. Rigvir significantly (P<0.05) prolonged survival in substage IB-IIC melanoma patients following surgery compared with patients who were under observation (according to current guidelines). The hazard ratio for patients under observation versus treated with Rigvir was statistically significantly different: hazard ratio 6.27 for all, 4.39 for substage IIA-IIB-IIC and 6.57 for substage IIB-IIC patients. The follow-up period was not statistically different between both treatment groups. These results indicate that the patients treated with Rigvir had a 4.39-6.57-fold lower mortality than those under observation. In this study, there was no untoward side effect or discontinuation of Rigvir treatment. Safety assessment of adverse events graded according to NCI CTCAE did not show any value above grade 2 in Rigvir-treated patients. In conclusion, Rigvir significantly prolongs survival in early-stage melanoma patients without any side effect.

Growth Hormone Treatment Improves Cognitive Function in Short Children with Growth Hormone Deficiency.

BACKGROUND/AIMS: We investigated the association between cognition and growth hormone (GH) status and GH treatment in short prepubertal children with broadly ranging GH secretion. METHODS: A total of 99 children (age 3-11 years), 41 with GH deficiency (GHD) and 58 with idiopathic short stature (ISS), were randomized to a fixed dose (43 µg/kg/day) or a prediction model-guided individualized dose (17-100 µg/kg/day) and followed up for 24 months. In a longitudinal and mixed within- and between-subjects study, we examined clinical effect size changes, measured by Cohen's d, in full-scale IQ (FSIQ) and secondary IQ indices. RESULTS: Significant increases giving medium effect size in FSIQ (p = 0.001, Cohen's d = 0.63), performance IQ (p = 0.001, Cohen's d = 0.65) and processing speed (p = 0.005, Cohen's d = 0.71) were found in the GH-deficient group. In contrast, perceptual organization only increased in the ISS group (p = 0.001, Cohen's d = 0.53). Baseline IQ was normally distributed with small but significant differences between the groups: GH-deficient children had lower FSIQ (p = 0.042) and lower performance IQ (p = 0.021). Using multiple regression analysis, 40% of the variance in delta processing speed scores (0-24 months) was explained by GHmax and IGF-ISDS at baseline. CONCLUSION: IQ, specifically fluid intelligence, increased in the GH-deficient children. The pretreatment status of the GH/IGF-I axis was significantly predictive for these changes. © 2015 S. Karger AG, Basel.

Isoallopregnanolone antagonize allopregnanolone-induced effects on saccadic eye velocity and self-reported sedation in humans.

Allopregnanolone (AP) is an endogenous neurosteroid. It modulates the effect of γ-amino-butyric acid (GABA) on the GABA type A (GABAA) receptor, which leads to increased receptor activity. Since the GABA-system is mainly inhibitory, increased AP activity leads to modulation of neuronal activity. In vitro studies of GABAA receptor activity and in vivo animal studies of sedation have shown that AP-induced effects can be inhibited by another endogenous steroid, namely isoallopregnanolone (ISO). In this study we investigated if ISO can antagonize AP-induced effects in healthy female volunteers, via measurements of saccadic eye velocity (SEV) and self-rated sedation. With a single-blind cross-over design, 12 women were studied on three separate occasions; given AP alone or AP in combination with one of two ISO doses. Congruent with previous reports, AP administration decreased SEV and induced sedation and these effects were diminished by simultaneous ISO administration. Also, the ISO effect modulation was seemingly stronger for SEV than for sedation. These effects were observed already at an ISO dose exposure that was approximately half of that of AP. In conclusion, ISO antagonized AP-induced decrease in SEV and self-reported sedation, probably in a non-competitive manner.

Growth hormone dose-dependent pubertal growth: a randomized trial in short children with low growth hormone secretion.

BACKGROUND/AIMS: Growth hormone (GH) treatment regimens do not account for the pubertal increase in endogenous GH secretion. This study assessed whether increasing the GH dose and/or frequency of administration improves pubertal height gain and adult height (AH) in children with low GH secretion during stimulation tests, i.e. idiopathic isolated GH deficiency. METHODS: A multicenter, randomized, clinical trial (No. 88-177) followed 111 children (96 boys) at study start from onset of puberty to AH who had received GH 33 µg/kg/day for ≥1 year. They were randomized to receive 67 µg/kg/day (GH(67)) given as one (GH(67×1); n = 35) or two daily injections (GH(33×2); n = 36), or to remain on a single 33 µg/kg/day dose (GH(33×1); n = 40). Growth was assessed as heightSDSgain for prepubertal, pubertal and total periods, as well as AHSDS versus the population and the midparental height. RESULTS: Pubertal heightSDSgain was greater for patients receiving a high dose (GH(67), 0.73) than a low dose (GH(33×1), 0.41, p < 0.05). AHSDS was greater on GH(67) (GH(67×1), -0.84; GH(33×2), -0.83) than GH(33) (-1.25, p < 0.05), and heightSDSgain was greater on GH(67) than GH(33) (2.04 and 1.56, respectively; p < 0.01). All groups reached their target heightSDS. CONCLUSION: Pubertal heightSDSgain and AHSDS were dose dependent, with greater growth being observed for the GH(67) than the GH(33) randomization group; however, there were no differences between the once- and twice-daily GH(67) regimens. © 2014 S. Karger AG, Basel.

IGF-1 and growth response to adult height in a randomized GH treatment trial in short non-GH-deficient children.

CONTEXT: GH treatment significantly increased adult height (AH) in a dose-dependent manner in short non-GH-deficient children in a randomized, controlled, clinical trial; the mean gain in height SD score (heightSDS) was 1.3 (range 0-3), compared with 0.2 in the untreated group. OBJECTIVE: The objective of the study was to analyze the relationship between IGF-1SDS, IGF binding protein-3 SDS (IGFBP3SDS), and their ratioSDS with a gain in the heightSDS until AH in non-GH-deficient short children. DESIGN AND SETTING: This was a randomized, controlled, multicenter clinical trial. INTERVENTION: The intervention included GH treatment: 33 or 67 µg/kg · d plus untreated controls. SUBJECTS: One hundred fifty-one non-GH-deficient short children were included in the intent-to-treat (ITT) population and 108 in the per-protocol (PP) population; 112 children in the ITT and 68 children in the PP populations had idiopathic short stature (ISS). MAIN OUTCOME MEASURES: Increments from baseline to on-treatment study mean IGF-1SDS (ΔIGF-1SDS), IGFBP3SDS, and IGF-1 to IGFBP3 ratioSDS were assessed in relationship to the gain in heightSDS. RESULTS: Sixty-two percent of the variance in the gain in heightSDS in children on GH treatment could be explained by four variables: ΔIGF-1SDS (explaining 28%), bone age delay, birth length (the taller the better), and GH dose (the higher the better). The lower IGF-1SDS was at baseline, the higher was its increment during treatment. For both the AllPP- and the ISSPP-treated groups, the attained IGF-1SDS study level did not correlate with height gain. CONCLUSION: In short non-GH-deficient children, the GH dose-related increment in IGF-1SDS from baseline to mean study level was the most important explanatory variable for long-term growth response from the peripubertal period until AH, when IGF-1SDS, IGFBP3SDS, and their ratioSDS were compared concurrently.

Reduced morbidity at diagnosis and improved glycemic control in children previously enrolled in DiPiS follow-up.

AIMS/HYPOTHESIS: Children participating in longitudinal type 1 diabetes prediction studies were reported to have less severe disease at diabetes diagnosis. Our aim was to investigate children who from birth participated in the Diabetes Prediction in Skåne (DiPiS) study for metabolic status at diagnosis and then continued to be followed for 2 yr of regular clinical care. METHODS: Children, followed in DiPiS before diagnosis, were compared to children in the same birth cohort, who did not participate in follow-up. Metabolic status, symptoms at diagnosis as well as hemoglobin A1c (HbA1c) and doses of insulin at 3, 6, 12, and 24 months after diagnosis were compared. RESULTS: Children, followed in DiPiS and diagnosed at 2-12 yr of age, had 0.8% (9 mmol/mol) lower HbA1c at diagnosis than those who were not followed (p = 0.006). At diagnosis, fewer DiPiS children had symptoms (p = 0.014) and ketoacidosis at diagnosis were reduced (2% compared to 18%, p = 0.005). During regular clinical care, HbA1c levels for the DiPiS children remained lower both at 12 (0.4% (4 mmol/mol); p = 0.009) and 24 months (0.8% (9 mmol/mol) p < 0.001) after diagnosis, despite no difference in total daily insulin between the two groups. CONCLUSIONS: Participation in prospective follow-up before diagnosis of type 1 diabetes leads to earlier diagnosis with fewer symptoms, decreased incidence of ketoacidosis as well as better metabolic control up to 2 yr after diagnosis. Our data indicate that metabolic control at the time of diabetes diagnosis is important for early metabolic control possibly affecting the risk of long-term complications.

Psychological and social outcome of epilepsy in well-functioning children and adolescents. A 10-year follow-up study.

BACKGROUND: From a population based study of epilepsy in Swedish children a subgroup designated well-functioning with an epilepsy diagnosis in 1997 was worked up from a medical point of view 10 years later. AIM: To describe the psychological and social outcome in this subgroup. METHODS: Thirty-one patients aged 11-22 years and their parents/partners responded to a questionnaire according to Achenbach System of Empirically Based Assessment (ASEBA) to evaluate behavioural and emotional problems, and social competence. RESULTS: Active epilepsy, diagnosed in 32%, was related to attention problems, somatic complaints, and school problems. Polytherapy, used in 16%, was related to attention problems and aggressive behaviour. School problems were found in six of seven children younger than 18 years. Internalizing, externalizing, and 'other' syndromes were found in 29% of the individuals, but a grouping of these syndromes in the clinical range only in two (6.5%), a girl with generalized tonic-clonic seizures alone, and a boy with structural focal epilepsy. Both had active epilepsy and were treated with polytherapy. All ten individuals with Rolandic epilepsy were classified as normal. The answers to the ASEBA questionnaire of individuals and parents/partners were inconsistent, and parents generally stated more problems than the individuals. SUMMARY: This 10-year follow-up study of psychological and social outcome in well-functioning children and adolescents with childhood onset epilepsy shows some emotional, behavioural, and social problems. Thus, early information to increase knowledge about epilepsy and associated psychological co-morbidities in order to decrease risk of low self-esteem, social anxiety, and depression later in life is of importance.

The cost-effectiveness of growth hormone replacement therapy (Genotropin®) in hypopituitary adults in Sweden.

BACKGROUND: To evaluate the cost-effectiveness of growth hormone (GH) treatment (Genotropin®) compared with no GH treatment in adults with GH deficiency in a Swedish societal setting. METHODS: A Markov-type cost-utility simulation model was constructed and used to simulate, for men and women, morbidity and mortality for GH-treated and -untreated individuals over a 20-year period. The calculations were performed using current available prices concerning morbidity-related healthcare costs and costs for Genotropin®. All costs and treatment effects were discounted at 3%. Costs were expressed in Euro (1€ = 9.03 SEK). GH-treated Swedish patients (n = 434) were identified from the KIMS database (Pfizer International Metabolic Database) and untreated patients (n = 2135) from the Swedish Cancer Registry and the Hospital Discharge Registry. RESULTS: The results are reported as incremental cost per quality-adjusted life year (QALY) gained, including both direct and indirect costs for GH-treated versus untreated patients. The weighted sum of all subgroup incremental cost per QALY was €15,975 and €20,241 for men and women, respectively. Including indirect cost resulted in lower cost per QALY gained: €11,173 and €10,753 for men and women, respectively. Key drivers of the results were improvement in quality of life, increased survival, and intervention cost. CONCLUSIONS: The incremental cost per QALY gained is moderate when compared with informal thresholds applied in Sweden. The simulations suggest that GH-treatment is cost-effective for both men and women at the €55,371 (SEK 500,000 - the informal Swedish cost-effectiveness threshold) per QALY threshold.

Early electrophysiological abnormalities and clinical neuropathy: a prospective study in patients with type 1 diabetes.

OBJECTIVE: The aim of this study was to elucidate whether subclinical nerve dysfunction as reflected by neurophysiological testing predicts the development of clinical neuropathy in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: Fifty-nine patients were studied twice with neurophysiological measurements at baseline and at follow-up. At baseline, patients were 15.5±3.22 years (range 7-22 years) of age, and duration of diabetes was 6.8±3.3 years. At follow-up, patients were 20-35 years of age, and disease duration was 20±5.3 years (range 10-31 years). RESULTS: At baseline, patients showed modestly reduced nerve conduction velocities and amplitudes compared with healthy subjects, but all were free of clinical neuropathy. At follow-up, clinical neuropathy was present in nine (15%) patients. These patients had a more pronounced reduction in peroneal motor nerve conduction velocity (MCV), median MCV, and sural sensory nerve action potential at baseline (P<0.010-0.003). In simple logistic regression analyses, the predictor with the strongest association with clinical neuropathy was baseline HbA1c (R2=48%, odds ratio 7.9, P<0.002) followed by peroneal MCV at baseline (R2=38%, odds ratio 0.6, P<0.006). With the use of a stepwise forward analysis that included all predictors, first baseline HbA1c and then only peroneal MCV at baseline entered significantly (R2=61%). Neuropathy impairment assessment showed a stronger correlation with baseline HbA1c (ρ=0.40, P<0.002) than with follow-up HbA1c (ρ=0.034, P<0.007). CONCLUSIONS: Early defects in nerve conduction velocity predict the development of diabetic neuropathy. However, the strongest predictor was HbA1c during the first years of the disease.

Relationship between Ljungan virus antibodies, HLA-DQ8, and insulin autoantibodies in newly diagnosed type 1 diabetes children.

Environmental factors, including viral infections, may explain an increasing and fluctuating incidence of childhood type 1 diabetes (T1D). Ljungan virus (LV) isolated from bank voles have been implicated, but it is unclear whether LV contributes to islet autoimmunity, progression to clinical onset, or both, of T1D. The aim was to test whether LV antibodies (LVAb) were related to HLA-DQ and islet autoantibodies in newly diagnosed T1D patients (n=676) and controls (n=309). Patients, 0-18 years of age, diagnosed with T1D in 1996-2005 were analyzed for LVAb, HLA-DQ genotypes, and all seven known islet autoantibodies (GADA, IA-2A, IAA, ICA, ZnT8RA, ZnT8WA, and ZnT8QA). LVAb at 75(th) percentile, defined as cut off, was 90 (range 6-3936) U/mL and 4(th) quartile LVAb were found in 25% (170/676) of which 64% were <10 (n=108, p<0.0001), and 27% were<5 (n=45; p<0.0001) years old. The 4(th) quartile LVAb in children <10 years of age correlated to HLA DQ2/8, 8/8, and 8/X (p<0.0001). Furthermore, in the group with 4(th) quartile LVAb, 55% were IAA positive (p=0.01) and correlation was found between 4(th) quartile LVAb and IAA in children <10 years of age (p=0.035). It is concluded that 1) LVAb were common among the young T1D patients and LVAb levels were higher in the younger age groups; 2) 4(th) quartile LVAb correlated with IAA; and 3) there was a correlation between 4(th) quartile LVAb and HLA-DQ8, particularly in the young patients. The presence of LVAb supports the notion that prior exposure to LV may be associated with T1D.

Glucose tolerance and beta-cell function in islet autoantibody-positive children recruited to a secondary prevention study.

AIMS: Children with type 1 diabetes (T1D) risk and islet autoantibodies are recruited to a secondary prevention study. The aims were to determine metabolic control in relation to human leukocyte antigen (HLA) genetic risk and islet autoantibodies in prepubertal children. METHODS: In 47 healthy children with GADA and at least one additional islet autoantibody, intravenous glucose tolerance test (IvGTT) and oral glucose tolerance test (OGTT) were performed 8-65 d apart. Hemoglobin A1c, plasma glucose as well as serum insulin and C-peptide were determined at fasting and during IvGTT and OGTT. RESULTS: All children aged median 5.1 (4.0-9.2) yr had autoantibodies to two to six of the beta-cell antigens GAD65, insulin, IA-2, and the three amino acid position 325 variants of the ZnT8 transporter. In total, 20/47 children showed impaired glucose metabolism. Decreased (≤ 30 µU/mL insulin) first-phase insulin response (FPIR) was found in 14/20 children while 11/20 had impaired glucose tolerance in the OGTT. Five children had both impaired glucose tolerance and FPIR ≤ 30 µU/mL insulin. Number and levels of autoantibodies were not associated with glucose metabolism, except for an increased frequency (p = 0.03) and level (p = 0.01) of ZnT8QA in children with impaired glucose metabolism. Among the children with impaired glucose metabolism, 13/20 had HLA-DQ2/8, compared to 9/27 of the children with normal glucose metabolism (p = 0.03). CONCLUSION: Secondary prevention studies in children with islet autoantibodies are complicated by variability in baseline glucose metabolism. Evaluation of metabolic control with both IvGTT and OGTT is critical and should be taken into account before randomization. All currently available autoantibody tests should be analyzed, including ZnT8QA.