Anxiety and Risk Perception in Parents of Children Identified by Population Screening as High Risk for Type 1 Diabetes.

OBJECTIVE: To assess anxiety and risk perception among parents whose children screened positive for islet autoantibodies, indicating elevated risk for type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: The Autoimmunity Screening for Kids (ASK) study identified 319 children age 1 to 17 years at risk for T1D via screening for islet autoantibodies; 280 children with confirmed islet autoantibodies and their caregivers enrolled in a follow-up education and monitoring program to prevent diabetic ketoacidosis at diagnosis. Parents completed questionnaires at each monitoring visit, including a 6-item version of the State Anxiety Inventory (SAI), to assess anxiety about their child developing T1D, and a single question to assess risk perception. RESULTS: At the first ASK follow-up monitoring visit, mean parental anxiety was elevated above the clinical cutoff of 40 (SAI 46.1 ± 11.2). At the second follow-up monitoring visit (i.e., visit 2), mean anxiety remained elevated but started to trend down. Approximately half (48.9%) of parents reported their child was at increased risk for T1D at the initial follow-up monitoring visit (visit 1). Parents of children with more than one islet autoantibody and a first-degree relative with T1D were more likely to report their child was at increased risk. CONCLUSIONS: Most parents of autoantibody-positive children have high anxiety about their child developing T1D. Information about the risk of developing T1D is difficult to convey, as evidenced by the wide range of risk perception reported in this sample.

Toll-Like Receptor 4 Plays a Significant Role in the Biochemical and Neurological Alterations Observed in Two Distinct Mice Models of Huntington's Disease.

Toll-like receptors (TLRs) are central players in innate immunity responses. They are expressed in glial cells and neurons, and their overactivation leads to the production of proinflammatory molecules, neuroinflammation, and neural damage associated with many neurodegenerative pathologies, such as Huntington's disease (HD). HD is an inherited disorder caused by a mutation in the gene coding for the protein Huntingtin (Htt). Expression of mutated Htt (mHtt) causes progressive neuronal degeneration characterized by striatal loss of GABAergic neurons, oxidative damage, neuroinflammatory processes, and impaired motor behavior. The main animal models to study HD are the intrastriatal injection of quinolinic acid (QA) and the transgenic B6CBA-Tg (HDexon1)61Gpb/1 J mice (R6/1). Those models mimic neuronal damage and systemic manifestations of HD. The objective of this work was to study the participation of TLR4 in the manifestations of neuronal damage and HD symptoms in the two mentioned models. For this purpose, C57BL6/J and TLR4-KO mice were administered with QA, and after that motor activity, and neuronal and oxidative damages were measured. R6/1 and TLR4-KO were mated to study the effect of low expression of TLR4 on the phenotype manifestation in R6/1 mice. We found that TLR4 is involved in motor activity, and neurological and oxidative damage induced by intrastriatal injection of QA, and the low expression of TLR4 causes a delay in the onset of phenotypic manifestations by the mHtt expression in R6/1 mice. Our results show that TLR4 is involved in both models of HD and focuses then as a therapeutic target for some deleterious reactions in HD.

Determinants of health-related quality of life in elderly ovarian cancer patients: The role of frailty and dependence.

OBJECTIVE: To investigate the impact of frailty and dependence on health-related quality of life (HRQOL) in elderly women diagnosed with epithelial ovarian cancer (EOC). METHODS: Data was gathered from a prospectively collected data biobank, OncoLifeS (Oncological Life Study) at the University Medical Center of Groningen. Women with a diagnosis of EOC, ≥65 years of age, with baseline assessment available from January 2016 to May 2018 were included. HRQOL was determined using the EORTC QLQ-C30 yielding scores on Global Health Status, five functional scales, three symptom scales, and six single items. The summary score was also calculated. Frailty was measured using the Groningen Frailty Indicator (GFI), and dependence using the Instrumental Activities of Daily Living (IADL). To evaluate the impact of frailty and dependence on HRQOL, linear regression was performed. Analyses were adjusted for age and tumor stage. RESULTS: 84 patients were included. Median age was 71 years (IQR: 68-75), 78% had advanced stage and 81% serous histology. Overall, the median global health status was 67 (IQR: 50-83). HRQOL scales with lowest scores were: role functioning (median: 66.7; IQR: 33-100), fatigue (median: 33.3; IQR: 22-56) and insomnia (median: 33.3; IQR: 0-67). Being frail was associated with worse functioning on all HRQOL scales and higher symptom scores (p = .001). Conversely, being independent was associated with better functioning on all HRQOL scales and lower symptom scores. These associations remained significant after adjusting for age and tumor stage. CONCLUSION: In women ≥65 years, diagnosed with EOC, frailty and dependence are associated to reduced HRQOL. These associations remain significant adjusting for age and stage.

Serum Uromodulin Predicts Less Coronary Artery Calcification and Diabetic Kidney Disease Over 12 Years in Adults With Type 1 Diabetes: The CACTI Study.

OBJECTIVE: Novel biomarkers are needed to better predict coronary artery calcification (CAC), a marker of subclinical atherosclerosis, and diabetic kidney disease (DKD) in type 1 diabetes. We evaluated the associations between serum uromodulin (SUMOD [a biomarker associated with anti-inflammatory and renal protective properties]), CAC progression, and DKD development over 12 years. RESEARCH DESIGN AND METHODS: Participants (n = 527, 53% females) in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study were examined during 2002-2004, at a mean age of 39.6 ± 9.0 years and a median duration of diabetes of 24.8 years. Urine albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) determined by the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine equation were measured at baseline and after a mean follow-up period of 12.1 ± 1.5 years. Elevated albumin excretion was defined as ACR ≥30 mg/g, rapid GFR decline (>3 mL/min/1.73 m2/year), and impaired GFR as eGFR <60 mL/min/1.73 m2. SUMOD was measured on stored baseline plasma samples (Meso Scale Discovery). CAC was measured using electron beam computed tomography. CAC progression was defined as a change in the square root-transformed CAC volume of ≥2.5. RESULTS: Higher baseline SUMOD level conferred lower odds of CAC progression (odds ratio 0.68; 95% CI 0.48-0.97), incident elevated albumin excretion (0.37; 0.16-0.86), rapid GFR decline (0.56; 0.35-0.91), and impaired GFR (0.44; 0.24-0.83) per 1 SD increase in SUMOD (68.44 ng/mL) after adjustment for baseline age, sex, systolic blood pressure, LDL cholesterol, and albuminuria/GFR. The addition of SUMOD to models with traditional risk factors also significantly improved the prediction performance for CAC progression and incident DKD. CONCLUSIONS: Higher baseline SUMOD level predicted lower odds of both CAC progression and incident DKD over 12 years in adults with type 1 diabetes.

Anion exchanger 3 in dorsal root ganglion contributes to nerve injury-induced chronic mechanical allodynia and thermal hyperalgesia.

OBJECTIVE: To determine the role of anion exchanger 3 (AE3) in dorsal root ganglion (DRG) in nerve injury-induced chronic nociception in the rat. METHODS: Spared nerve injury (SNI) was used to induce neuropathic pain. Von Frey filaments and Hargreaves test were used to assess tactile allodynia and thermal hyperalgesia, respectively. Drugs were given by intrathecal administration. Western blotting was used to determine AE3 expression in DRG. KEY FINDINGS: SNI produced long-lasting mechanical allodynia and thermal hyperalgesia. AE3 was found in DRG of sham-operated rats. SNI enhanced baseline AE3 expression in L4 and L5 DRGs at days 7 and 14, respectively. In contrast, SNI did not affect AE3 expression in L6 DRG. AE3 expression returned to baseline levels 21 days after SNI. Intrathecal 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) (5-50 µg) pretreatment prevented SNI-induced allodynia and, at a lesser extent, hyperalgesia. Moreover, DIDS (50 µg) reduced SNI-induced AE3 upregulation in L4, but not L5, DRGs. Intrathecal DIDS (5-50 µg) or anti-AE3 antibody (1 µg), but not vehicle, post-treatment (6 days) partially reversed SNI-induced allodynia and hyperalgesia. DIDS or anti-AE3 antibody post-treatment diminished SNI-induced AE3 upregulation in L4 and L5 DRGs. CONCLUSIONS: Data suggest that AE3 is present in DRG and contributes to mechanical allodynia and thermal hyperalgesia in neuropathic rats.

Predictability of BRCA1/2 mutation status in patients with ovarian cancer: How to select women for genetic testing in middle-income countries.

OBJECTIVES: To evaluate the accuracy of algorithms for predicting BRCA1/2 germ-line mutation carrier probability, and to identify factors that could improve their performance among Brazilian women with ovarian cancer (OC). STUDY DESIGN: In this cross-sectional study, we enrolled patients (unselected for family history of cancer) undergoing treatment or follow-up for OC in a single centre in Brazil. Clinical and demographic data, including family history of cancer, were obtained. Blood samples were collected for genetic testing. MAIN OUTCOME MEASURES: The entire coding sequence of BRCA1 and BRCA2 was evaluated for mutations. Mutation carrier probability was calculated using BOADICEA, BRCAPRO, Myriad and the Manchester score. Sensitivity, specificity, positive and negative predictive values, and area under the receiver operating characteristic curves (AUC) were calculated for each algorithm. Logistic regression was used to detect additional factors associated with BRCA1/2 status, and these were added to the algorithms before recalculating the AUCs. RESULTS: BRCA1/2 mutations were identified in 19 of the 100 included patients. BOADICEA outperformed other algorithms (sensitivity, 73.7%; specificity, 87.7%; AUC, 0.87, with a threshold of a 10% risk of mutation). Later menarche was associated with the presence of a BRCA1/2 mutation. Although adding age at menarche resulted in a larger AUC for all models, this increase was significant only for the Myriad algorithm. CONCLUSION: A BOADICEA risk evaluation of 10% or more most accurately predicted BRCA1/2 status, and the inclusion of age at menarche tended to improve the performance of all algorithms. Using these tools could reduce the number of tests, but at the expense of missing a significant proportion of mutation carriers.

Maternal Origin and Risk of Neonatal and Maternal ICU Admission.

OBJECTIVES: To evaluate maternal world region of birth, as well as maternal country of origin, and the associated risk of admission of 1) a mother to a maternal ICU, 2) her infant to a neonatal ICU, or 3) both concurrently to an ICU. DESIGN: Retrospective population-based cohort study. SETTING: Entire province of Ontario, Canada, from 2003 to 2012. PATIENTS: All singleton maternal-child pairs who delivered in any Ontario hospital. MEASUREMENTS AND MAIN RESULTS: We explored how maternal world region of birth, and specifically, maternal country of birth for the top 25 countries, was associated with the outcome of 1) neonatal ICU, 2) maternal ICU, and 3) both mother and newborn concurrently admitted to ICU. Relative risks were adjusted for maternal age, parity, income quintile, chronic hypertension, diabetes mellitus, obesity, dyslipidemia, drug dependence or tobacco use, and renal disease. Compared with infants of Canadian-born mothers (110.7/1,000), the rate of neonatal ICU admission was higher in immigrants from South Asia (155.2/1,000), Africa (140.4/1,000), and the Caribbean (167.3/1,000; adjusted relative risk, 1.41; 95% CI, 1.36-1.46). For maternal ICU, the adjusted relative risk was 1.79 (95% CI, 1.43-2.24) for women from Africa and 2.21 (95% CI, 1.78-2.75) for women from the Caribbean. Specifically, mothers from Ghana (adjusted relative risk, 2.71; 95% CI, 1.75-4.21) and Jamaica (adjusted relative risk, 2.74; 95% CI, 2.12-3.53) were at highest risk of maternal ICU admission. The risk of both mother and newborn concurrently admitted to ICU was even more pronounced for Ghana and Jamaica. CONCLUSIONS: Women from Africa and the Caribbean and, in particular, Ghana and Jamaica, are at higher risk of admission to ICU around the time of delivery, as are their newborns.

Reduced Bone Mineral Density Is Associated with Celiac Disease Autoimmunity in Children with Type 1 Diabetes.

OBJECTIVE: To evaluate the association between bone mineral density (BMD), glycemic control (hemoglobin A1c [HbA1c]), and celiac autoimmunity in children with type 1 diabetes mellitus (T1D) and in an appropriate control population. STUDY DESIGN: BMD was assessed cross-sectionally in 252 children with T1D (123 positive for anti-tissue transglutaminase antibody [tTGA] and 129 matched children who were negative for tTGA). In addition, BMD was assessed in 141 children without diabetes who carried T1D-associated HLD-DR, DQ genotypes (71 positive for tTGA and 70 negative). RESULTS: Children with T1D who were positive for tTGA had significantly worse BMD L1-L4 z-score compared with children with T1D who were negative for tTGA (-0.45 ± 1.22 vs 0.09 ± 1.10, P = .0003). No differences in growth measures, urine N-telopeptides, 25-hydroxyvitamin D, ferritin, thyroid stimulating hormone, or HbA1c were found. However, both higher HbA1c (ß = -1.25 ± 0.85, P = .0016) and tTGA (ß = -0.13 ± 0.05, P = .0056) were significant and independent predictors of lower BMD in multivariate analyses. No differences in BMD or other variables measured were found between children without diabetes who were positive vs negative for tTGA. CONCLUSIONS: The results suggest a synergistic effect of hyperglycemia and celiac autoimmunity on low BMD.

Predictors of Progression From the Appearance of Islet Autoantibodies to Early Childhood Diabetes: The Environmental Determinants of Diabetes in the Young (TEDDY).

OBJECTIVE: While it is known that there is progression to diabetes in <10 years in 70% of children with two or more islet autoantibodies, predictors of the progression to diabetes are only partially defined. RESEARCH DESIGN AND METHODS: The Environmental Determinants of Diabetes in the Young (TEDDY) study has observed 8,503 children who were at increased genetic risk for autoimmune diabetes. Insulin autoantibodies (IAAs), GAD65 autoantibodies (GADAs), and insulinoma-associated protein 2 autoantibodies (IA-2As) were measured every 3 months until 4 years of age and every 6 months thereafter; if results were positive, the autoantibodies were measured every 3 months. RESULTS: Life table analysis revealed that the cumulative incidence of diabetes by 5 years since the appearance of the first autoantibody differed significantly by the number of positive autoantibodies (47%, 36%, and 11%, respectively, in those with three autoantibodies, two autoantibodies, and one autoantibody, P < 0.001). In time-varying survival models adjusted for first-degree relative status, number of autoantibodies, age at first persistent confirmed autoantibodies, and HLA genotypes, higher mean IAA and IA-2A levels were associated with an increased risk of type 1 diabetes in children who were persistently autoantibody positive (IAAs: hazard ratio [HR] 8.1 [95% CI 4.6-14.2]; IA-2A: HR 7.4 [95% CI 4.3-12.6]; P < 0.0001]). The mean GADA level did not significantly affect the risk of diabetes. CONCLUSIONS: In the TEDDY study, children who have progressed to diabetes usually expressed two or more autoantibodies. Higher IAA and IA-2A levels, but not GADA levels, increased the risk of diabetes in those children who were persistently autoantibody positive.

Early hyperglycemia detected by continuous glucose monitoring in children at risk for type 1 diabetes.

OBJECTIVE: We explore continuous glucose monitoring (CGM) as a new approach to defining early hyperglycemia and diagnosing type 1 diabetes in children with positive islet autoantibodies (Ab+). RESEARCH DESIGN AND METHODS: Fourteen Ab+ children, free of signs or symptoms of diabetes, and nine antibody-negative (Ab-) subjects, followed by the Diabetes Autoimmunity Study in the Young, were asked to wear a Dexcom SEVEN CGM. RESULTS: The Ab+ subjects showed more hyperglycemia, with 18% time spent above 140 mg/dL, compared with 9% in Ab- subjects (P = 0.04). Their average maximum daytime glucose value was higher, and they had increased glycemic variability. The mean HbA1c in the Ab+ subjects was 5.5% (37 mmol/mol). Among Ab+ subjects, ≥18-20% CGM time spent above 140 mg/dL seems to predict progression to diabetes. CONCLUSIONS: CGM can detect early hyperglycemia in Ab+ children who are at high risk for progression to diabetes. Proposed CGM predictors of progression to diabetes require further validation.

Insulin sensitivity and insulin clearance are heritable and have strong genetic correlation in Mexican Americans.

OBJECTIVE: The GUARDIAN (Genetics UndeRlying DIAbetes in HispaNics) consortium is described, along with heritability estimates and genetic and environmental correlations of insulin sensitivity and metabolic clearance rate of insulin (MCRI). METHODS: GUARDIAN is comprised of seven cohorts, consisting of 4,336 Mexican-American individuals in 1,346 pedigrees. Insulin sensitivity (SI ), MCRI, and acute insulin response (AIRg) were measured by frequently sampled intravenous glucose tolerance test in four cohorts. Insulin sensitivity (M, M/I) and MCRI were measured by hyperinsulinemic-euglycemic clamp in three cohorts. Heritability and genetic and environmental correlations were estimated within the family cohorts (totaling 3,925 individuals) using variance components. RESULTS: Across studies, age, and gender-adjusted heritability of insulin sensitivity (SI , M, M/I) ranged from 0.23 to 0.48 and of MCRI from 0.35 to 0.73. The ranges for the genetic correlations were 0.91 to 0.93 between SI and MCRI; and -0.57 to -0.59 for AIRg and MCRI (all P < 0.0001). The ranges for the environmental correlations were 0.54 to 0.74 for SI and MCRI (all P < 0.0001); and -0.16 to -0.36 for AIRg and MCRI (P < 0.0001-0.06). CONCLUSIONS: These data support a strong familial basis for insulin sensitivity and MCRI in Mexican Americans. The strong genetic correlations between MCRI and SI suggest common genetic determinants.

Cultural-geographical differences in the occurrence of child physical abuse? A meta-analysis of global prevalence.

Our comprehensive meta-analysis combined prevalence figures of child physical abuse reported in 111 studies, including 168 independent samples with a total of 9,698,801 participants. The overall estimated prevalence was 3/1000 for studies using informants and 226/1000 for studies using self-report measures of child physical abuse, with no apparent gender differences. Methodological factors partly explained the vast variation of self-reported prevalence rates in individual studies. The highest prevalence rates were found for studies using a broad definition of child physical abuse, studies measuring physical abuse over the longest period of 0-18 years, studies using college samples, studies in which adults served as respondents, and studies using more questions on physical abuse. Cultural-geographical factors did not seem to affect prevalence rates of physical abuse, which may be partly due to procedural factors. More crosscultural research on physical abuse is badly needed, especially in Africa and South America. We conclude that child physical abuse is a widespread, global phenomenon affecting the lives of millions of children all over the world, which is in sharp contrast with the United Nation's Convention on the Rights of the Child.

Historical microbiology: revival and phylogenetic analysis of the luminous bacterial cultures of M. W. Beijerinck.

Luminous bacteria isolated by Martinus W. Beijerinck were sealed in glass ampoules in 1924 and 1925 and stored under the names Photobacterium phosphoreum and 'Photobacterium splendidum'. To determine if the stored cultures were viable and to assess their evolutionary relationship with currently recognized bacteria, portions of the ampoule contents were inoculated into culture medium. Growth and luminescence were evident after 13 days of incubation, indicating the presence of viable cells after more than 80 years of storage. The Beijerinck strains are apparently the oldest bacterial cultures to be revived from storage. Multi-locus sequence analysis, based on the 16S rRNA, gapA, gyrB, pyrH, recA, luxA, and luxB genes, revealed that the Beijerinck strains are distant from the type strains of P. phosphoreum, ATCC 11040(T), and Vibrio splendidus, ATCC 33125(T), and instead form an evolutionarily distinct clade of Vibrio. Newly isolated strains from coastal seawater in Norway, France, Uruguay, Mexico, and Japan grouped with the Beijerinck strains, indicating a global distribution for this new clade, designated as the beijerinckii clade. Strains of the beijerinckii clade exhibited little sequence variation for the seven genes and approximately 6300 nucleotides examined despite the geographic distances and the more than 80 years separating their isolation. Gram-negative bacteria therefore can survive for many decades in liquid storage, and in nature, they do not necessarily diverge rapidly over time.

Decreasing incidence and severity of cerebral palsy in prematurely born children.

OBJECTIVE: To examine incidence and severity of cerebral palsy (CP), and associated factors among preterm survivors (gestational age <34 weeks), admitted to a neonatal intensive care unit from 1990-2005. STUDY DESIGN: Eighteen antenatal, perinatal and postnatal factors were analyzed. The cohort was divided in four birth periods: 1990-1993 (n=661), 1994-1997 (n=726), 1998-2001 (n=723), and 2002-2005 (n=850). The Gross Motor Function Classification System was used as primary outcome measure (mean age: 32.9 ± 5.3 months). Logistic regression analyses were used. RESULTS: CP incidence decreased from 6.5% in period I, to 2.6%, 2.9% and 2.2% (P<.001) in period II-IV, respectively. Simultaneously, cystic periventricular leukomalacia (c-PVL) decreased from 3.3% in period I to 1.3% in period IV (P=.004). Within the total cohort (n=3287), c-PVL grade III decreased from 2.3% in period I to 0.2% in period IV (P=.003). The number of children with Gross Motor Function Classification System levels III-V decreased from period I to IV (P=.035). Independent risk factors for CP were c-PVL and severe intraventricular hemorrhage, whereas antenatal antibiotics, presence of an arterial line, Caesarean section, and gestational age were independent protective factors. CONCLUSION: CP incidence and severity decreased from 1990-1993 onward, which could be attributed to a reduction of 93% in severe c-PVL.

Serial MRI and neurodevelopmental outcome in 9- to 10-year-old children with neonatal encephalopathy.

OBJECTIVE: To assess the relation between patterns of brain injury on neonatal and childhood magnetic resonance imaging (MRI) and long-term neurodevelopmental outcome. STUDY DESIGN: Neonatal (n = 34) and childhood MRIs (n = 77) were analyzed for 80 children with neonatal encephalopathy and for 51 control subjects during childhood. MRIs were graded as normal, mildly abnormal (white matter lesions), or moderately/severely abnormal (watershed injury, lesions in basal ganglia/thalamus or focal infarction). Severity of brain injury was related to different aspects of neurologic outcome: Total impairment score of the Movement Assessment Battery for Children, intelligence quotient score, cerebral palsy, postneonatal epilepsy, and need for special education. Seven children with neonatal encephalopathy required extracorporeal membrane oxygenation treatment. RESULTS: Neonatal and childhood MRI were comparable in 25/33 children (75.8%, P < .001). Children with moderate/severe lesions on neonatal or childhood MRI more often had a total impairment score

Need for quantitative assessment of transglutaminase autoantibodies for celiac disease in screening-identified children.

OBJECTIVES: To assess several transglutaminase autoantibody (TGAA) assays in their ability to distinguish celiac disease (CD) in screening-identified children with abnormal intestine biopsy specimens from those with normal biopsy specimens. STUDY DESIGN: Children at risk for CD (n = 54) composed of type 1 diabetics, first-degree relatives of type 1 diabetics or CD, and HLA-DQ2+ individuals followed from birth received intestine biopsy. Sera obtained at the time of biopsy were tested for TGAA, using the radioimmunoassay and 5 other commercially available enzyme-linked immunosorbent assays. RESULTS: False-positive rates ranged from 28% to 80%. The positive predictive value (PPV) of the tests ranged from 63% to 84% (lower than reported for symptomatic children). Setting a higher cutoff for each assay maximized PPV. CONCLUSIONS: There are significant quantitative differences among all TGAA assays that could affect interpretation of a positive test for CD. The overall false-positive rate for all assays was high in this population. Using the assay as a quantitative rather than qualitative tool by increasing the cutoff of positivity to indicate biopsy increases PPV. Multicenter workshops are needed to identify critical differences and to standardize TGAA assays among laboratories.

Association between folic acid food fortification and congenital orofacial clefts.

By January 1998, most of Canada's cereal grain products were being fortified with folic acid. Among 336963 women who underwent antenatal maternal serum screening, the prevalence of orofacial clefts did not change from before (1.15 per 1000) to after (1.21 per 1000) food fortification (prevalence ratio, 1.06; 95% confidence interval, 0.86-1.30).