Seroprevalence study of SARS-CoV-2 antibodies in healthcare workers following the first wave of the COVID-19 pandemic in a tertiary-level hospital in the south of Ireland.

OBJECTIVE: This study investigated seroprevalence of SARS-CoV-2-specific IgG antibodies, using the Abbott antinucleocapsid IgG chemiluminescent microparticle immunoassay (CMIA) assay, in five prespecified healthcare worker (HCW) subgroups following the first wave of the COVID-19 pandemic. SETTING: An 800-bed tertiary-level teaching hospital in the south of Ireland. PARTICIPANTS: Serum was collected for anti-SARS-CoV-2 nucleocapsid IgG using the Abbott ARCHITECT SARS-CoV-2 IgG CMIA qualitative assay, as per the manufacturer's specifications.The groups were as follows: (1) HCWs who had real-time PCR (RT-PCR) confirmed COVID-19 infection (>1-month postpositive RT-PCR); (2) HCWs identified as close contacts of persons with COVID-19 infection and who subsequently developed symptoms (virus not detected by RT-PCR on oropharyngeal/nasopharyngeal swab); (3) HCWs identified as close contacts of COVID-19 cases and who remained asymptomatic (not screened by RT-PCR); (4) HCWs not included in the aforementioned groups working in areas determined as high-risk clinical areas; and (5) HCWs not included in the aforementioned groups working in areas determined as low-risk clinical areas. RESULTS: Six of 404 (1.49%) HCWs not previously diagnosed with SARS-CoV-2 infection (groups 2-5) were seropositive for SARS-CoV-2 at the time of recruitment into the study.Out of the 99 participants in group 1, 72 had detectable IgG to SARS-CoV-2 on laboratory testing (73%). Antibody positivity correlated with shorter length of time between RT-PCR positivity and antibody testing.Quantification cycle value on RT-PCR was not found to be correlated with antibody positivity. CONCLUSIONS: Seroprevalence of SARS-CoV-2 antibodies in HCWs who had not previously tested RT-PCR positive for COVID-19 was low compared with similar studies.

Glycemic Outcome Associated With Insulin Pump and Glucose Sensor Use in Children and Adolescents With Type 1 Diabetes. Data From the International Pediatric Registry SWEET.

OBJECTIVE: Insulin delivery methods, glucose-monitoring modalities, and related outcomes were examined in a large, international, diverse cohort of children and adolescents with type 1 diabetes from the Better Control in Pediatric and Adolescent Diabetes: Working to Create Centers of Reference (SWEET) -Registry. RESEARCH DESIGN AND METHODS: Participants with type 1 diabetes of ≥1 year, aged ≤18 years, and who had documented pump or sensor usage during the period August 2017-July 2019 were stratified into four categories: injections-no sensor (referent); injections + sensor; pump-no sensor; and pump + sensor. HbA1c and proportion of patients with diabetic ketoacidosis (DKA) or severe hypoglycemia (SH) were analyzed; linear and logistic regression models adjusted for demographics, region, and gross domestic product per capita were applied. RESULTS: Data of 25,654 participants were analyzed. The proportions of participants (adjusted HbA1c data) by study group were as follows: injections-no sensor group, 37.44% (8.72; 95% CI 8.68-8.75); injections + sensor group, 14.98% (8.30; 95% CI 8.25-8.35); pump-no sensor group, 17.22% (8.07; 95% CI 8.03-8.12); and pump + sensor group, 30.35% (7.81; 95% CI 7.77-7.84). HbA1c was lower in all categories of participants who used a pump and/or sensor compared with the injections-no sensor treatment method (P < 0.001). The proportion of DKA episodes was lower in participants in the pump + sensor (1.98%; 95% CI 1.64-2.48; P < 0.001) and the pump-no sensor (2.02%; 95% CI 1.64-2.48; P < 0.05) groups when compared with those in the injections-no sensor group (2.91%; 95% CI 2.59-3.31). The proportion of participants experiencing SH was lower in pump-no sensor group (1.10%; 95% CI 0.85-1.43; P < 0.001) but higher in the injections + sensor group (4.25%; 95% CI 3.65-4.95; P < 0.001) compared with the injections-no sensor group (2.35%; 95% CI 2.04-2.71). CONCLUSIONS: Lower HbA1c and fewer DKA episodes were observed in participants using either a pump or continuous glucose monitoring (CGM) or both. Pump use was associated with a lower rate of SH. Across SWEET centers, use of pumps and CGM is increasing. The concomitant use of pump and CGM was associated with an additive benefit.

Proportion of Basal to Total Insulin Dose Is Associated with Metabolic Control, Body Mass Index, and Treatment Modality in Children with Type 1 Diabetes-A Cross-Sectional Study with Data from the International SWEET Registry.

OBJECTIVES: To investigate in a large population the proportion of daily basal insulin dose (BD) to daily total insulin dose (TD) (BD/TD) and its association with glycated hemoglobin A1c (HbA1c), body mass index (BMI)- SDS, and treatment modality in children with type 1 diabetes. STUDY DESIGN: Cross-sectional study in subjects with type 1 diabetes, age ≤18 years, and ≥2 years of diabetes duration, registered in the international multicenter Better control in Pediatric and Adolescent diabeteS: Working to crEate CEnTers of Reference registry in March 2018. Variables included region, sex, age, diabetes duration, treatment modality (multiple daily injections [MDI] or continuous subcutaneous insulin infusion [CSII]), self-monitoring blood glucose, HbA1c, BD/TD, and BMI-SDS. BMI was converted to BMI-SDS using World Health Organization charts as reference. Hierarchic linear regression models were applied with adjustment for age, sex, and diabetes duration. RESULTS: A total of 19 687 children with type 1 diabetes (49% female, 49% CSII users) with median age 14.8 (11.5; 17.2) years and diabetes duration 6.0 (3.9; 9.0) years were included. HbA1c was 63 (55; 74) mmol/mol (7.9 [7.2; 8.9]%), and BMI-SDS 0.55 (-0.13; 1.21). Unadjusted, a lower BD/TD was associated with lower HbA1c, male sex, younger age, shorter diabetes duration, lower BMI-SDS, higher numbers of self-monitoring blood glucose and CSII (all P < .01). After adjustment for confounders, lower BD/TD was associated with lower HbA1c (P < .01) and lower BMI-SDS (P < .01) in children on CSII, but not on MDI. CONCLUSIONS: Lower BD/TD is positively associated with lower HbA1c and lower BMI-SDS in children with type 1 diabetes on CSII. It remains to be investigated in a prospective study whether reducing BD/TD insulin will improve metabolic control and normalize body weight in children with type 1 diabetes.

A description of clinician reported diagnosis of type 2 diabetes and other non-type 1 diabetes included in a large international multicentered pediatric diabetes registry (SWEET).

BACKGROUND: Although type 1 diabetes (T1D) remains the most frequent form of diabetes in individuals aged less than 20 years at onset, other forms of diabetes are being increasingly recognized. OBJECTIVES: To describe the population of children with other forms of diabetes (non-type 1) included in the multinational SWEET (Better control in Pediatric and Adolescent diabeteS: Working to crEate CEnTers of Reference) database for children with diabetes. METHODS: Cases entered in the SWEET database are identified by their physician as T1D, type 2 diabetes (T2D) and other types of diabetes according to the ISPAD classification. Etiologic subgroups are provided for other types of diabetes. Descriptive analyses were tabulated for age at onset, gender, daily insulin doses, and hemoglobin A1c (A1C) for each type and subtype of diabetes and when possible, values were compared. RESULTS: Of the 27 104 patients included in this report, 95.5% have T1D, 1.3% T2D, and 3.2% other forms of diabetes. The two most frequent etiologies for other forms of diabetes were maturity onset diabetes of the young (MODY) (n = 351) and cystic fibrosis-related diabetes (CFRD) (n = 193). The cause was unknown or unreported in 10% of other forms of diabetes. Compared with T1D, children with T2D and CFRD were diagnosed at an older age, took less insulin and had lower A1C (all P < .0001). CONCLUSION: In centers included in SWEET, forms of diabetes other than type 1 remain rare and at times difficult to characterize. Sharing clinical information and outcome between SWEET centers on those rare forms of diabetes has the potential to improve management and outcome.

Insulin pump therapy in children with type 1 diabetes: analysis of data from the SWEET registry.

BACKGROUND: Intensified insulin delivery using multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) is recommended in children with type 1 diabetes (T1D) to achieve good metabolic control. OBJECTIVE: To examine the frequency of pump usage in T1D children treated in SWEET (Better control in Paediatric and Adolescent diabeteS: Working to crEate CEnTers of Reference) centers and to compare metabolic control between patients treated with CSII vs MDI. METHODS: This study included 16 570 T1D children participating in the SWEET prospective, multicenter, standardized diabetes patient registry. Datasets were aggregated over the most recent year of treatment for each patient. Data were collected until March 2016. To assess the organization of pump therapy a survey was carried out. RESULTS: Overall, 44.4% of T1D children were treated with CSII. The proportion of patients with pump usage varied between centers and decreased with increasing age compared with children treated with MDI. In a logistic regression analysis adjusting for age, gender and diabetes duration, the use of pump was associated with both: center size [odd ratio 1.51 (1.47-1.55), P < .0001) and the diabetes-related expenditure per capita [odd ratio 1.55 (1.49-1.61), P < .0001]. Linear regression analysis, adjusted for age, gender, and diabetes duration showed that both HbA1c and daily insulin dose (U/kg/d) remained decreased in children treated with CSII compared to MDI (P < .0001). CONCLUSIONS: Insulin pump therapy is offered by most Sweet centers. The differences between centers affect the frequency of use of modern technology. Despite the heterogeneity of centers, T1D children achieve relatively good metabolic control, especially those treated with insulin pumps and those of younger age.

The value of in vitro studies in a case of neonatal diabetes with a novel Kir6.2-W68G mutation.

In infants, especially with novel previously undescribed mutations of the KATP channel causing neonatal diabetes, in vitro studies can be used to both predict the response to sulphonylurea treatment and support a second trial of glibenclamide at higher than standard doses if the expected response is not observed.

Urinary conjugated α-tocopheronolactone--a biomarker of oxidative stress in children with type 1 diabetes.

Increased oxidative stress has been implicated in both the onset and the progression of diabetes mellitus and its complications. The development of easy to measure biomarkers of oxidative stress would, therefore, help in determining in a prospective manner the impact of glycemic control on oxidative stress and macrovascular disease in patients with diabetes. We report the development and validation of a novel method to directly measure the urinary concentrations of the conjugated metabolites of vitamin E (α-tocopherol) and investigate whether the oxidized metabolite α-tocopheronolactone (α-TL) could be used as a biomarker of oxidative stress in children with type 1 diabetes. A novel method using liquid chromatography-tandem mass spectrometry was developed and used to measure directly and rapidly the urinary concentrations of the glucuronidated and sulfated metabolites of α-tocopherol in 32 young patients with type 1 diabetes and age-matched controls. The mean concentrations of the glucuronidated and sulfated conjugates of α-TL were all highly significantly increased in the children with type 1 diabetes (p<0.001). The results suggest that the measurement of the urinary concentrations of α-TL conjugates may provide a useful biomarker of oxidative stress in diabetes and possibly in other clinical conditions in which oxidative stress has been implicated.

Genotype-phenotype analysis in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency.

CONTEXT: P450 oxidoreductase deficiency (PORD) is a unique congenital adrenal hyperplasia variant that manifests with glucocorticoid deficiency, disordered sex development (DSD), and skeletal malformations. No comprehensive data on genotype-phenotype correlations in Caucasian patients are available. OBJECTIVE: The objective of the study was to establish genotype-phenotype correlations in a large PORD cohort. DESIGN: The design of the study was the clinical, biochemical, and genetic assessment including multiplex ligation-dependent probe amplification (MLPA) in 30 PORD patients from 11 countries. RESULTS: We identified 23 P450 oxidoreductase (POR) mutations (14 novel) including an exonic deletion and a partial duplication detected by MLPA. Only 22% of unrelated patients carried homozygous POR mutations. p.A287P was the most common mutation (43% of unrelated alleles); no other hot spot was identified. Urinary steroid profiling showed characteristic PORD metabolomes with variable impairment of 17α-hydroxylase and 21-hydroxylase. Short cosyntropin testing revealed adrenal insufficiency in 89%. DSD was present in 15 of 18 46,XX and seven of 12 46,XY individuals. Homozygosity for p.A287P was invariably associated with 46,XX DSD but normal genitalia in 46,XY individuals. The majority of patients with mild to moderate skeletal malformations, assessed by a novel scoring system, were compound heterozygous for missense mutations, whereas nearly all patients with severe malformations carried a major loss-of-function defect on one of the affected alleles. CONCLUSIONS: We report clinical, biochemical, and genetic findings in a large PORD cohort and show that MLPA is a useful addition to POR mutation analysis. Homozygosity for the most frequent mutation in Caucasians, p.A287P, allows for prediction of genital phenotype and moderate malformations. Adrenal insufficiency is frequent, easily overlooked, but readily detected by cosyntropin testing.

Pubertal presentation in seven patients with congenital adrenal hyperplasia due to P450 oxidoreductase deficiency.

CONTEXT: P450 oxidoreductase (POR) is a crucial electron donor to all microsomal P450 cytochrome (CYP) enzymes including 17α-hydroxylase (CYP17A1), 21-hydroxylase (CYP21A2) and P450 aromatase. Mutant POR causes congenital adrenal hyperplasia with combined glucocorticoid and sex steroid deficiency. P450 oxidoreductase deficiency (ORD) commonly presents neonatally, with disordered sex development in both sexes, skeletal malformations, and glucocorticoid deficiency. OBJECTIVE: The aim of the study was to describe the clinical and biochemical characteristics of ORD during puberty. DESIGN: Clinical, biochemical, and genetic assessment of seven ORD patients (five females, two males) presenting during puberty was conducted. RESULTS: Predominant findings in females were incomplete pubertal development (four of five) and large ovarian cysts (five of five) prone to spontaneous rupture, in some only resolving after combined treatment with estrogen/progestin, GnRH superagonists, and glucocorticoids. Pubertal development in the two boys was more mildly affected, with some spontaneous progression. Urinary steroid profiling revealed combined CYP17A1 and CYP21A2 deficiencies indicative of ORD in all patients; all but one failed to mount an appropriate cortisol response to ACTH stimulation indicative of adrenal insufficiency. Diagnosis of ORD was confirmed by direct sequencing, demonstrating disease-causing POR mutations. CONCLUSION: Delayed and disordered puberty can be the first sign leading to a diagnosis of ORD. Appropriate testosterone production during puberty in affected boys but manifest primary hypogonadism in girls with ORD may indicate that testicular steroidogenesis is less dependent on POR than adrenal and ovarian steroidogenesis. Ovarian cysts in pubertal girls may be driven not only by high gonadotropins but possibly also by impaired CYP51A1-mediated production of meiosis-activating sterols due to mutant POR.

Cystic fibrosis-related diabetes in childhood.

Since the early 1990s the management of children with cystic fibrosis (CF) has come a long way and advances in both nutritional and medical care have resulted in a median age of survival of 30-35 years, as compared with a life expectancy of <1 year in the 1950s. The first definitive reports of glucose intolerance or diabetes in CF are from 1955. The combination of CF and related diabetes (CFRD) has a negative impact on survival. CFRD is now the most common complication of CF (50% of the CF patients will develop diabetes by the age of 30 years), and is associated with a 6-fold increase in morbidity and mortality. CFRD is usually asymptomatic and can remain undetected for up to 4 years prior to diagnosis. The objective of this report was to review the current literature (Medline and Pubmed searches) on CFRD in children and adolescents and provide a comprehensive report of incidence, prevalence and pathophysiology of insulin deficiency and insulin insensitivity. Along with survival and prognosis in CFRD the current management strategies in the diagnosis, monitoring and treatment of CFRD will also be addressed.

Validation of continuous glucose monitoring in children and adolescents with cystic fibrosis: a prospective cohort study.

OBJECTIVE: To validate continuous glucose monitoring (CGM) in children and adolescents with cystic fibrosis. RESEARCH DESIGN AND METHODS: Paired oral glucose tolerance tests (OGTTs) and CGM monitoring was undertaken in 102 children and adolescents with cystic fibrosis (age 9.5-19.0 years) at baseline (CGM1) and after 12 months (CGM2). CGM validity was assessed by reliability, reproducibility, and repeatability. RESULTS: CGM was reliable with a Bland-Altman agreement between CGM and OGTT of 0.81 mmol/l (95% CI for bias +/- 2.90 mmol/l) and good correlation between the two (r = 0.74-0.9; P < 0.01). CGM was reproducible with no significant differences in the coefficient of variation of the CGM assessment between visits and repeatable with a mean difference between CGM1 and CGM2 of 0.09 mmol/l (95% CI for difference +/- 0.46 mmol/l) and a discriminant ratio of 13.0 and 15.1, respectively. CONCLUSIONS: In this cohort of children and adolescents with cystic fibrosis, CGM performed on two occasions over a 12-month period was reliable, reproducible, and repeatable.

Homozygous nonsense and frameshift mutations of the ACTH receptor in children with familial glucocorticoid deficiency (FGD) are not associated with long-term mineralocorticoid deficiency.

OBJECTIVE: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease characterized by isolated glucocorticoid deficiency with preserved mineralocorticoid secretion. Mutations in the ACTH receptor (MC2R) account for approximately 25% of all FGD cases, but since these are usually missense mutations, a degree of receptor function is frequently retained. A recent report, however, suggested that disturbances in the renin-aldosterone axis were seen in some patients with potentially more severe MC2R mutations. Furthermore, MC2R knock out mice have overt aldosterone deficiency and hyperkalaemia despite preservation of a normal zona glomerulosa. We wished to determine whether a group of patients with severe nonsense mutations of the MC2R exhibited evidence of mineralocorticoid deficiency, thereby challenging the conventional diagnostic feature of FGD which might result in diagnostic misclassification. DESIGN: Clinical review of patients with nonsense MC2R mutations. PATIENTS: Between 1993 and 2008, 164 patients with FGD were screened for mutations in the MC2R. Totally 42 patients (34 families) were found to have mutations in the MC2R. Of these, 6 patients (4 families) were found to have homozygous nonsense or frameshift mutations. RESULTS: Mild disturbances in the renin-angiotensin-aldosterone axis were noted in four out of six patients, ranging from slightly elevated plasma renin levels to low aldosterone levels, although frank mineralocorticoid deficiency or electrolyte disturbance were not found. No patient required fludrocortisone replacement. CONCLUSION: Severe nonsense and frameshift MC2R mutations are not associated with clinically significant mineralocorticoid deficiency and are thus unlikely to require long-term mineralocorticoid replacement.

A novel variant of familial glucocorticoid deficiency prevalent among the Irish Traveler population.

CONTEXT: Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder characterized by distinct clinical, biochemical, and genetic abnormalities. The prevalence of FGD is unknown, with the likelihood that cases remain undiagnosed. We noted a significant proportion of our FGD cases are Irish Travelers. Irish Travelers are an endogamous nomadic group ethnically and genetically distinct from Roma gypsies. AIMS: The objective of the study was to describe the clinical features and assess the prevalence of FGD amongst Irish Travelers in the Republic of Ireland and describe their phenotype. METHODS: Diagnosis of FGD was based on clinical features, high ACTH, and low cortisol concentrations with normal renin and aldosterone concentrations and exclusion of other causes of adrenal failure. Data from the Republic of Ireland Census 2006 were used. RESULTS: We identified 21 cases of FGD, generating an overall prevalence of one in 201,898. We report nine Irish Travelers (five females) with FGD related to a new gene negative for melanocortin-2 receptor and melanocortin-2 receptor accessory protein mutations. Of a total population of 22,557 Travelers, this yields a disease prevalence of one in 2506 with a carrier frequency of one in 25 in this group and represents a prevalence of one in 665 and a carrier frequency of one in 13 in the 4- to 15-yr Traveler age group. All nine children had a later onset of FGD due to the fact that their initial investigations revealed normal cortisol (422-575 nmol/liter) and ACTH (<34 ng/liter) concentrations. CONCLUSION: We report a high prevalence of FGD among Irish Travelers. Their subtle phenotype and initial normal biochemistry may delay the early diagnosis of FGD.