Optimal 25-OH-Vitamin D Level in Children Derived From Biochemical Parameters.

The aim of the study was to evaluate the bone-optimal pediatric levels of 25-hydroxy-vitamin D (25OHD) by testing the level at which 25OHD optimally effects calcium, phosphorus, and parathyroid hormone levels in a large population-based dataset. This was an observational retrospective "big-data" study. We analyzed 49 935 25OHD tests from children sampled in Clalit Health Services, Jerusalem district between 2009 and 2019. Associated data were available in the following number of samples: corrected calcium; 18 869, phosphorus: 1241, and PTH: 449. We tested correlations between each parameter and 25OHD, adjusting phosphorus levels by age using a "phosphorus index". Pearson's and Spearman's correlation coefficients were calculated to determine the strength of the correlation between 25OHD and each parameter. There was a significant correlation between 25OHD levels and both PTH and calcium but not for the phosphorus index. The level at which increase in 25OHD continued to cause significant alteration was: for PTH up to 100 nmol/l (40 ng/ml), for corrected calcium it increased beyond 100 nmol/l. Increasing levels of 25OHD levels up to at least 100 nmol/l are associated with improvement in parameters known to be associated with increased bone mineralization. Therefore, one should aim for a 25OHD level of 100 nmo/l.

Linear growth of children with X-linked hypophosphatemia treated with burosumab: a real-life observational study.

To assess the long-term efficacy of burosumab for pediatric patients with X-linked hypophosphatemia, focusing on linear growth. This multi-center retrospective study included 35 pediatric patients who began treatment with burosumab between January 2018 and January 2021. We collected clinical data, anthropometric measurements, laboratory results, and Rickets Severity Score (RSS), from 2 years prior to treatment initiation and up to 4 years after. Burosumab was initiated at a mean age of 7.5 ± 4.4 years (range 0.6-15.9), with a mean initial dose of 0.8 ± 0.3 mg/kg, which was subsequently increased to 1.1 ± 0.4 mg/kg. The patients were followed for 2.9 ± 1.4 years (range 1-4) after initiating burosumab. Serum phosphorus levels increased from 2.7 ± 0.8 mg/dl at burosumab initiation to 3.4 ± 0.6 mg/dl after 3 months and remained stable (p < 0.001). Total reabsorption of phosphorus increased from 82.0 ± 6.8 to 90.1 ± 5.3% after 12 months of treatment (p = 0.041). The RSS improved from 1.7 ± 1.0 at burosumab initiation to 0.5 ± 0.6 and 0.3 ± 0.6 after 12 and 24 months, respectively (p < 0.001). Both height z-score and weight z-score improved from burosumab initiation to the end of the study: from - 2.07 ± 1.05 to - 1.72 ± 1.04 (p < 0.001) and from - 0.51 ± 1.12 to - 0.11 ± 1.29 (p < 0.001), respectively. Eight children received growth hormone combined with burosumab treatment. Height z-score improved among those who received growth hormone (from - 2.33 ± 1.12 to - 1.94 ± 1.24, p = 0.042) and among those who did not (from - 2.01 ± 1.01 to - 1.66 ± 1.01, p = 0.001). CONCLUSION:  Burosumab treatment in a real-life setting improved phosphate homeostasis and rickets severity and enhanced linear growth. WHAT IS KNOWN: • Compared to conventional therapy, burosumab treatment has been shown to increase serum phosphate levels and reduce the severity of rickets. • The effect of burosumab on growth is still being study. WHAT IS NEW: • Height z-score improved between the start of burosumab treatment and the end of the study (-2.07 ± 1.05 vs. -1.72 ± 1.04, p < 0.001). • Eight children received burosumab combined with growth hormone treatment without side effects during the concomitant treatments.

Is TSH a Reliable Indicator of Thyroid Hormone Status in Pregnancy?

Thyroid screening is recommended during pregnancy with serum thyrotropin (TSH) as the primary test. However, since human chorionic gonadotropin, the serum hallmark of pregnancy, has TSH-like effects, the adequacy of TSH as a screening tool in this constellation requires further study. This study aimed to evaluate the relationship between TSH and thyroid hormones during pregnancy in order to determine if TSH is an adequate screening tool. This was a retrospective study utilizing the Clalit Health Service, Jerusalem district database between 2006-2017 in which we analyzed TSH, FT4 and FT3 measurements from 32430 pregnancies resulting in live birth. We grouped FT4 and FT3 levels by trimester and by the following TSH levels: (1) below 0.1/0.2/0.3 mIU/l, (2) 0.1-2.5/0.2-3.0/0.3-3.0 mIU/l, (3) 2.6-4.0/3.1-4.0 mIU/l, (4) 4.1-10.0 mIU/l and (5) above 10.0 mIU/l. In the first trimester, the most important for fetal brain development, FT3 was below normal, defined as below the 2.5th percentile for the population, in only 15.3% of tests with TSH over 10 mIU/l. FT4 was below normal in only 12.8% of such tests. Similar findings were noted for the second and third trimesters. As expected, there were far less abnormal tests when lower TSH cutoff levels were tested. In conclusion, TSH levels beyond the range accepted as normal do not, in most cases, reflect abnormal thyroid hormone levels during pregnancy. TSH is not a good screen for overt hypothyroidism in pregnancy. This may be due, at least in the first trimester, to thyrotropic effects of HCG.

Alarming increase in ketoacidosis in children and adolescents with newly diagnosed type 1 diabetes during the first wave of the COVID-19 pandemic in Israel.

OBJECTIVE: To evaluate the incidence and severity of ketoacidosis (DKA) at type 1 diabetes diagnosis during the first wave of the coronavirus disease 2019 (COVID-19) pandemic in Israel. RESEARCH DESIGN AND METHODS: A population-based study the product of a national collaboration of Israeli pediatric diabetes centers investigated the presentation of childhood-onset type 1 diabetes. The frequencies of DKA and severe DKA observed during the COVID-19 period from March 15, 2020 (commencement of the first nationwide lockdown) until June 30, 2020 were compared with the same periods in 2019, 2018, and 2017 using multivariable logistic regression, adjusting for age, sex, and socioeconomic position. RESULTS: During the COVID-19 period, DKA incidence was 58.2%, significantly higher than in 2019 (adjusted OR [aOR] 2.18 [95% CI, 1.31-3.60], P = 0.003); 2018 (aOR 2.05 [95% CI, 1.26-3.34], P = 0.004); and 2017 (aOR, 1.79 [95% CI, 1.09-2.93], P = 0.022). The incidence of severe DKA was 19.9%, significantly higher than in 2018 (aOR, 2.49 [95% CI, 1.20-5.19], P = 0.015) and 2017 (aOR, 2.73 [95% CI, 1.28-5.82], P = 0.009). In 2020, admissions and duration of stay in the intensive care unit were higher than in previous years (P = 0.001). During the COVID-19 pandemic, children aged 6-11 years had higher incidences of DKA (61.3% vs. 34.0%, 40.6%, and 45.1%, respectively, P = 0.012), and severe DKA (29.3% vs. 15.1%, 10.9%, and 5.9%, respectively, P = 0.002). CONCLUSIONS: The dramatic increase in DKA at presentation of childhood-onset type 1 diabetes during the COVID-19 pandemic mandates targeted measures to raise public and physician awareness.

Youth-onset type 2 diabetes in Israel: A national cohort.

BACKGROUND: Prevalence of youth-onset type 2 diabetes (T2D) has increased worldwide, paralleling the rise in pediatric obesity. Occurrence and clinical manifestations vary regionally and demographically. OBJECTIVES: We assessed the incidence, and clinical and demographic manifestations of youth-onset T2D in Israel. METHODS: In a national observational study, demographic, clinical, and laboratory data were collected from the medical records of children and adolescents, aged 10-18 years, diagnosed with T2D between the years 2008 and 2019. RESULTS: The incidence of youth-onset T2D in Israel increased significantly from 0.63/100,000 in 2008 to 3.41/100,000 in 2019. The study cohort comprised 379 individuals (228 girls [59.7%], 221 Jews [58.3%], mean age 14.7 ± 1.9 years); 73.1% had a positive family history of T2D. Mean body mass index (BMI) z-score was 1.96 ± 0.7, higher in Jews than Arabs. High systolic (≥ 130 mmHg) and diastolic blood pressure (≥ 85 mmHg) were observed in 33.7% and 7.8% of patients, respectively; mean glycosylated hemoglobin (A1c) level at diagnosis was 8.8 ± 2.5%. Dyslipidemia, with high triglyceride (>150 mg/dl) and low HDL-c (<40 mg/dl) levels, was found in 45.6% and 56.5%, respectively. Microalbuminuria and retinopathy were documented at diagnosis, 15.2% and 1.9%, respectively) and increased (36.7% and 4.6%, respectively) at follow-up of 2.9 ± 2.1 years. Criteria of metabolic syndrome were met by 224 (62.2%) patients, and fatty liver documented in 65%, mainly Jews. Psychosocial comorbidity was found in 31%. Treatment with metformin (45.6%), insulin (20.6%), and lifestyle modification (18%) improved glycemic control. CONCLUSION: Youth-onset T2D in Israel has increased significantly and presents a unique profile.

Clinical Criteria Can Identify Children With Osteopenia in Newly Diagnosed Crohn Disease.

OBJECTIVES: Chronic inflammation of Crohn disease (CD) is associated with reduced bone mineral density (BMD). As bone mass is almost exclusively accrued during childhood, early recognition of osteopenia is especially important in pediatric CD. We aimed to identify variables associated with osteopenia to guide dual-energy X-ray absorptiometry (DXA) scan screening to those who most need it. METHODS: This was a retrospective inception cohort study of children newly diagnosed with CD, and routinely referred to DXA scans. Demographic and explicit clinical data were recorded along with whole-body less head BMD, adjusted for age, sex, and height by z-scores. RESULTS: Of the 116 included children (mean age 13 ±â€Š3.1 years, 67 [58%] boys, mean body mass index [BMI] 16.7 ±â€Š2.6), 63 (54%) had normal BMD (z-score > -1) or borderline osteopenia (-1 ≥ z-score > -2) and 53 (46%) had osteopenia (z-score ≤ -2). Osteopenia was associated with lower BMI z-score (-0.8 ±â€Š1.2 vs -1.8 ±â€Š1.1, P < 0.001) and higher PCDAI (33.7 ±â€Š15.2 vs 25.7 ±â€Š16.5; P = 0.009) than those with BMD z-score >-2. In total, 59% of children with BMI z-score <-0.5 had moderate-severe osteopenia and only 18% of those with higher z-scores. Multivariate logistic regression identified BMI z-score as the sole risk factor (OR 1.28 [95% CI 1.08-1.52], P = 0.005). BMI z-score ≥-0.5 excludes osteopenia with a sensitivity 87%, specificity 49%, NPV 82%, and PPV 59%. CONCLUSIONS: Osteopenia was found in nearly half of children with newly onset CD. BMI z-score <-0.5 should prompt referral to DXA screening.

The Effect of Nutritional Therapy on Bone Mineral Density and Bone Metabolism in Pediatric Crohn Disease.

OBJECTIVES: Both the inflammatory burden of Crohn disease (CD) and corticosteroids have a negative effect on bone density. Exclusive enteral nutrition (EEN) avoids corticosteroids and promotes endoscopic healing. We aimed to explore the effect of nutritional therapy on bone health in pediatric CD. METHODS: This was a planned sub-study of a clinical trial enrolling children with new-onset mild-moderate CD. Children were randomized to either 6 weeks EEN followed by 6 weeks 25% partial enteral nutrition (PEN) or 6 weeks of 50% PEN with a CD exclusion diet followed by 6 weeks of 25% PEN with exclusion diet. Bone formation and resorption were measured at baseline, week 12 and week 24 by serum C-Propeptide of Type I Procollagen (CICP) and type I Collagen N-Telopeptide (NTX), respectively. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry (DXA) scan at baseline and week 24. RESULTS: Median CICP improved from 130 ng/mL (106-189) at baseline to 223 (143-258) at week 12 and 193 (143-252) at week 24 (P = 0.016 for both, n = 29 children). Median NTX remained unchanged (P = 0.45 and P = 0.45). Thirty-six children had DXA scans performed at diagnosis; 81% and 33% had z scores of <-1 and <-2, respectively. DXA z scores did not improve from baseline (adjusted total body less head [TBLH] BMD -1.62 ±â€Š0.87) to week 24 (-1.76 ±â€Š0.75; P = 0.30, n = 21 with both scans). CONCLUSIONS: Low bone density is common in new-onset mild-moderate pediatric CD. CICP, a sensitive marker of bone formation, improved following dietary intervention but this was not associated with improved BMD.

Celiac Disease and Celiac Antibodies in DM1 Patients: When Are Screening and Biopsy Recommended?

INTRODUCTION: The prevalence of celiac disease (CD) is increased in diabetes mellitus type 1 (DM1) patients. In most cases, CD is diagnosed in asymptomatic patients and hence periodic screening tests are recommended, but the timing, frequency of tests and indication for duodenal biopsy is unclear. The purpose of this study was to investigate the dynamics of CD serology in DM1 and identify risk factors for CD. METHODS: Celiac serology and duodenal biopsy results from 1990 until 2015 were collected from patients with DM1. The outcome of positive celiac serology, the incidence and risk factors for CD in DM1 patients were investigated. RESULTS: A total of 314 DM1 patients who had celiac serology were identified, with follow-up period up to 23 years. Of 31 patients (9.9%) with positive celiac serology, 11(35.4%) had spontaneous normalization after various time periods. Eighteen patients were diagnosed with CD (58.1% of positive celiac serology, 5.73% of the study cohort). Age under 4.5 years was a risk factor for CD, but not family background of autoimmune diseases or gender. All patients with CD diagnosis were diagnosed during the first 6 years following DM1 diagnosis. CONCLUSION: Screening asymptomatic DM1 patients for CD beyond 6 years after diagnosis is not recommended. Spontaneous normalization of CD serology occurs, and hence, serologic follow-up may be performed. In children with DM1 diagnosis under the age of 4.5 years or with positive CD serology at DM1 diagnosis, there is an increased risk for CD and therefore positive serology should lead to biopsy.

Levothyroxine Therapy Achieves Physiological FT3/FT4 Ratios at Higher than Normal TSH Levels: A Novel Justification for T3 Supplementation?

In euthyroidism, as thyroid Stimulating hormone (TSH) levels increase, the free triiodothyronine (FT3) to free thyroxine (FT4) ratio increases. The aim of this study was to assess if beyond the euthyroid range of TSH levels FT3/FT4 ratio continues to increase and if levothyroxine treatment reduces this ratio, possibly through TSH suppression. This cross sectional retrospective study included a total of 77 832 patients [age 22.76±15.17 years (4 days to 112 years)] evaluated and treated in community clinics between January 2009 and September 2013. Blood samples drawn in community clinics for which TSH, FT4, FT3, age, and gender were available were included. Tests with TSH below 0.5 IU/l were excluded as were samples taken during pregnancy. The FT3/FT4 ratio continued to increase significantly even with TSH above 50 mIU/l (p for trend<0.001) with an increase of more than 50% over the entire TSH range. With increasing age and female gender, the phenomenon was less prominent (p<0.001). Levothyroxine treated patients had significantly lower FT3/FT4 ratios in comparison to untreated patients up to TSH levels of 5.0 mIU/l. In conclusion, increasing TSH increases FT3/FT4 ratio even with severe hypothyroidism, less so with aging. With levothyroxine therapy, a ratio similar to untreated patients is achieved at TSH of above 5.0 mIU/l. Since T3 suppresses TSH better than T4, administration of T3 would likely normalize the FT3/FT4 ratio at a lower, ostensibly more physiological, TSH level. This could be seen as a rationale for add-on T3 therapy.

Lower Basal Insulin Dose is Associated with Better Control in Type 1 Diabetes.

OBJECTIVE: To test the hypothesis that lower basal insulin doses may be paradoxically associated with better diabetic control, we assessed the association between the basal insulin dose and hemoglobin A1c (HbA1c) level in a group of children and young adults with type 1 diabetes. STUDY DESIGN: This was a retrospective study of 89 patients with type 1 diabetes (mean age, 14.67 ± 4.8 years; range, 3-29 years) treated in a single outpatient clinic. Forty-six of the 89 patients were treated with continuous subcutaneous insulin infusion, and the other 43 were treated with multiple daily injections (glargine as basal insulin). The daily basal insulin dose was taken either as downloaded from the insulin pump or as registered in the chart at the most recent clinic visit. Glucose data were taken from computerized registration of downloaded patient glucometers. The mean time between data download and HbA1c determination was 0.9 ± 0.78 months. HbA1c level and basal insulin dose were entered with other variables in a multivariable linear regression model. RESULTS: There was a significant correlation between injection of less total daily basal insulin and lower HbA1c level (Pearson correlation, 0.441; P < .001). Optimal HbA1c level was associated with use of 0.28 ± 0.08 U/kg/day of basal insulin (35 ± 10% basal/total). CONCLUSION: With lower basal insulin levels, lower HbA1C was achieved despite the same total bolus dose. The optimal basal dose as determined by this study is similar to that found in fasting individuals of similar age.

FT3 IS HIGHER IN MALES THAN IN FEMALES AND DECREASES OVER THE LIFESPAN.

OBJECTIVE: Normal changes in free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) levels over the lifespan and differences between sexes are not well documented, mainly because even the largest-scale studies available include relatively small cohorts. The aim of this study was to define age-related trends including sex differences based on reliable data. METHODS: A large database including serum thyroid tests drawn in community clinics was studied. FT3, FT4, and TSH levels from 527,564 sera samples taken from patients age 1 year or greater were included. After highly extensive exclusion criteria applied to remove all samples that may have been taken from unhealthy people, 27,940 samples remained. These were stratified by decades of age and by sex. RESULTS: FT3 decreases throughout life, significantly more so among females, with equalization between sexes with greater age. FT4 declines to a lesser extent, also more among females than among males. Among the very old, females have higher levels of FT4. In contrast, TSH declines until age 50 and then increases slightly in both sexes. CONCLUSION: This study provides reliable data regarding trends in hormonal levels by age and sex, with the major finding being higher FT3 in males throughout life except in the very young and very old. These results have important implications for diagnosing and treating thyroid conditions. ABBREVIATIONS: ANOVA = analysis of variance; BMI = body mass index; FT3 = free triiodothyronine; FT4 = free thyroxine.

Normal limits for serum thyrotropin vary greatly depending on method.

CONTEXT: Thyroid-stimulating hormone (TSH) levels within populations do not follow Gaussian distribution, and normal limits are derived after mathematical normalization. The clinical relevance of these limits is unknown. The objective of this study was to compare upper and lower TSH limits by four data normalization methods with non-normalized data and assess their clinical relevance. DESIGN, PATIENTS AND MEASUREMENTS: Results of blood samples taken by community physicians and stored in a computerized database were analysed after removing samples from patients with evidence of thyroid illness. TSH values were normalized by the Hoffmann and Tukey methods and each method with natural log transformation. Non-normalized data for TSH in the uppermost and lowermost percentile were also calculated. Clinical relevance was determined by alterations in thyroid hormone levels at, below and above the limits for each method. RESULTS: The maximal reduction from non-normalized data for the upper normal limit (UNL) was by the Hoffman method 43% = 3·1 mIU/l). The maximal increase for the lower normal limit (LNL) was also by the Hoffman method (708% = 0·81 mIU/l). There was very limited difference in average FT3 and FT4 between patients with TSH within, below or above the normal range for all methods. CONCLUSIONS: Different normalization methods alter the normal limits greatly. However, in individuals without thyroid illness, thyroid hormone values are stable over a wide range of TSH levels including beyond the UNL for all methods. Indeed, there may be no true universal upper TSH cut-off level and clinical decision-making cannot rely on these calculated limits.

CLONIDINE STIMULATION TEST FOR GH DEFICIENCY: A NEW LOOK AT SAMPLE TIMING.

OBJECTIVE: In the glucagon stimulation test (GST), the occurrence of peak growth hormone (GH) levels at typical times is an indication of normal secretion. This has not been studied for the clonidine stimulation test (CST). The 120-minute time is rarely the peak, and previous reports suggest it can be omitted. This study aimed to evaluate the meaning and utility of peak time in the CST and the significance of shortening the test. METHODS: CSTs performed on 250 consecutive subjects in a single center were evaluated for results (GH sufficient or deficient) and result of confirmatory GST with respect to the peak time of the CST. RESULTS: Peak GH occurred typically at 30, 60, and 90 minutes (91.6% of tests, versus 60% expected) (P<.001). A total of 132 of 155 (85.15%) sufficient tests occurred at typical times, versus 66 of 97 (68%) deficient tests (P<.05). Typicality of timing did not follow in the confirmatory GST and did not predict the final result of testing. Removal of the 120-minute sample affected the final result in 0.4% of evaluations. CONCLUSION: The timing of the GH peak is not useful when interpreting the CST. The CST is equally effective when terminated at 90 minutes from stimulation.

The basal insulin dose; a lesson from prolonged fasting in young individuals with type 1 diabetes.

BACKGROUND AND OBJECTIVE: The insulin requirement for type 1 diabetes during prolonged fasting is unclear. In order to define this for clinical purposes, we investigated the total insulin dose associated with successful completion of a 25 h religious fast. SUBJECTS AND METHODS: Questionnaires were filled in during telephone interviews performed before and after 88 fasts in 57 young individuals with type 1 diabetes (age 20.4 ± 5.3, range: 12.3-31.2 yr). Duration of their diabetes was 8.7 ± 6.1 yr (range: 0.5-21.8) and latest HbA1c was 8.5 ± 1.9% (5.7-13.7). Twenty-eight patients fasted using multiple daily injections (MDI) and 30 were on continuous subcutaneous insulin infusion (CSII), including one who fasted in both categories. Subjects were instructed either to act as they had done for previous successful fasts or, for first-time fasts, to inject half their daily basal insulin injection or halve their basal CSII rate throughout the fast. The total daily insulin dose associated with successful completion of the fast was determined. RESULTS: Among those who completed the fast, average total insulin was 0.19 ± 0.16 U/kg, patients who discontinued their fast took on average 0.34 ± 0.15 U/kg. Seven MDI patients and 12 CSII patients terminated their fast early, mostly for mild hypoglycemia. No severe hypoglycemia or other serious adverse event occurred during any of the fasts. CONCLUSIONS: Fasting for 25 h is safe and can be undertaken in individuals with type 1 diabetes. The recommended total daily dose is 0.2 U/kg/day. This recommendation may possibly be used for other situations in which abstention from oral intake is required.

Time to menarche and final height after histrelin implant treatment for central precocious puberty.

OBJECTIVE: To compare final height, change in body mass index (BMI), and time from end of treatment until menarche in girls with central precocious puberty treated with the histrelin implant versus depot gonadotropin releasing hormone agonist injections. STUDY DESIGN: Chart review, interview, and final height measurements of 2 groups of girls with central precocious puberty; triptorelin depot (TD) group: 23 girls were treated from age 8.4 ± 0.3 with monthly injections of TD, for 26.7 ± 2.5 months; histrelin implant group: 11 girls were treated from age 8.7 ± 0.3 years for 28.4 ± 3.7 months, of whom 9 initially received monthly TD injections for 1.5-39 months. Final height, BMI (pretreatment vs recent), and time between either implant removal or last injection to menarche were compared. RESULTS: Time between removal of implant or last injection and menarche was 9.3 ± 1.5 (histrelin implant group) versus 16.1 ± 1.7 (TD group) months (P = .02). Predicted height at implant insertion was 156.8 ± 2.6 cm, and final height was 161.1 ± 2.0 cm (not significant [NS]). Predicted height for TD was 155.2 ± 1.9 cm and final height was 157.9 ± 1.7 cm (NS). Change from onset of treatment to final BMI-SDS for histrelin implant was -0.41 ± 0.3, and for TD was -0.03 ± 0.2 (NS). CONCLUSIONS: Menarche occurred sooner after implant removal. There was no difference in final height or BMI outcomes between the 2 treatment modalities.

Triptorelin depot stimulation test for central precocious puberty.

BACKGROUND: Acute gonadotropin responses following depot leuprolide acetate injection are useful for monitoring therapeutic efficacy in central precocious puberty. Similar monitoring of therapy in patients treated with another widely used GnRH agonist, depot triptorelin, has not yet been reported. OBJECTIVE: The objective of this study was to test the use of gonadotropin levels after therapeutic injections of depot triptorelin for evaluating efficacy of therapy. PATIENTS AND METHODS: Thirty-two patients (29 girls and three boys) were treated with triptorelin depot, 3.75 mg per vial, between 2006 and 2010. Treatment was initiated at 8.27±1.76 years (range, 4.6-11.6 years). Blood was drawn before and at variable times between 30 min and 2 h after injections. Clinical tests were retrospectively collected. RESULTS: After the first injection, the 60-min mean luteinizing hormone (LH) level was 21.6.1±18.0 IU/L and the follicle-stimulating hormone (FSH) was 13.5±3.6 IU/L. After subsequent injections, for those who showed clinical suppression, the standard deviations above the mean were 3.6 IU/L for FSH and 2.1 IU/L for LH. The LH levels of two patients who did not suppress sufficiently were at these limits or higher. CONCLUSIONS: Sixty-minute postinjection depot triptorelin levels of LH can be successfully used to evaluate the efficacy of treatment with this agent. Limits for suppressed levels have been determined.

Age and Gender Adjusted FT3 Levels as Novel Predictors of Survival.

CONTEXT: Lower levels of free T3 (FT3) occur during acute illness, as part of "euthyroid sick syndrome." A chronic form of this syndrome also exists. OBJECTIVE: To determine whether thyroid hormone levels predict long-term survival. DESIGN AND SETTING: This was a "big-data" study of thyroid function tests from samples taken between 2008 and 2014. Data were crossed with electronic health records for morbidity and mortality. Test results were converted to age- and gender-adjusted percentiles (AGAPs). The hazard ratio for death was crossed with ranges of initial AGAPs and change in AGAPs for 2 subgroups: "not healthy" (subjects with at least 1 of 5 chronic conditions registered in their electronic health chart) and "healthy" (all others). PARTICIPANTS: 2 453 091 sets of thyroid function tests from 365 965 distinct patients were evaluated. 258 695 sets remained after excluding patients registered as taking thyroid preparations or anti-thyroid drugs. MAIN OUTCOME MEASURE: Hazard ratio for death, planned before data collection. RESULTS: The cohort included 151 868 not healthy and 106 827 healthy people. After a median of 6.8 years, 5865/151 868 (10.4%) of the not healthy had died and 2504/106 827 (2.3%) of healthy participants. Low initial FT3 AGAPs were predictive of poor survival. The hazard ratio for survival compared between the lowest 5 and highest 50 percentiles of initial FT3 AGAPs for not healthy participants was 5.71 [confidence interval (CI) 5.23-6.26, P < .001] and for healthy was 3.92 (CI 3.06-5.02, P < .001). CONCLUSION: Low FT3 AGAPs predicted poor survival, most strongly among not healthy people.

Current normal values for TSH and FT3 in children are too low: evidence from over 11,000 samples.

BACKGROUND: Current pediatric normal values for thyroid function tests are based on data from relatively few patients. OBJECTIVE: To develop new normal pediatric values based on a large sample of children. PATIENTS AND METHODS: Data were collected from a computerized database in Jerusalem, Israel, of thyroid function tests taken in community pediatric clinics. Samples from patients with antithyroid peroxidase antibodies and/or antithyroglobulin antibodies and from those treated with levothyroxine, methimazole, propylthiouracil, thyrotropin, lithium, phenobarbital, or glucocorticoids were excluded. The analysis included over 11,000 samples tested for TSH, free triiodothyronine (FT3), and free thyroxine (FT4) with the ADVIA Centaur system. RESULTS: The upper normal limit (UNL) for TSH increased by about 1 mIU/L and the lower normal limit (LNL) for FT3 increased by 0.5-2 pmol/L in different age groups. There was no significant change in FT4 values. CONCLUSIONS: These reference data should replace current normal values.

Vitamin D deficiency is associated with higher risks for SARS-CoV-2 infection and COVID-19 severity: a retrospective case-control study.

Robust evidence of whether vitamin D deficiency is associated with COVID-19 infection and its severity is still lacking. The aim of the study was to evaluate the association between vitamin D levels and the risks of SARS-CoV-2 infection and severe disease in those infected. A retrospective study was carried out among members of Clalit Health Services (CHS), the largest healthcare organization in Israel, between March 1 and October 31, 2020. We created two matched case-control groups of individuals for which vitamin D levels and body mass index (BMI) were available before the pandemic: group (A), in which 41,757 individuals with positive SARS-CoV-2 PCR tests were matched with 417,570 control individuals without evidence of infection, and group (B), in which 2533 patients hospitalized in severe condition for COVID-19 were matched with 2533 patients who were tested positive for SARS-CoV-2, but were not hospitalized. Conditional logistic models were fitted in each of the groups to assess the association between vitamin D levels and outcome. An inverse correlation was demonstrated between the level of vitamin D and the risks of SARS-CoV-2 infection and of severe disease in those infected. Patients with very low vitamin D levels (< 30 nmol/L) had the highest risks for SARS-CoV-2 infection and also for severe COVID-19 when infected-OR 1.246 [95% CI 1.210-1.304] and 1.513 [95% CI 1.230-1.861], respectively. In this large observational population study, we show a significant association between vitamin D deficiency and the risks of SARS-CoV-2 infection and of severe disease in those infected.

Persistent hyperthyrotropinemia in congenital hypothyroidism: successful combination treatment with levothyroxine and liothyronine.

BACKGROUND: Some children with congenital hypothyroidism (CH), have persistent hyperthyrotropinemia despite good compliance with levothyroxine. OBJECTIVE: To evaluate combination therapy of liothyronine (cytomel) with levothyroxine in CH with persistent hyperthyrotropinemia. PATIENTS AND METHODS: Files were reviewed retrospectively. Eight female patients with persistently high levels of TSH and upper normal FT4 levels were given either 6.25 or 12 microg liothyronine and the levothyroxine dose was reduced appropriately. Pre- and post-intervention hormone levels and drug doses were evaluated. RESULTS: TSH decreased in 8/8 and normalized in 6/8 patients. FT4 and free tri-iodothyronine (FT3) remained normal. The levothyroxine-equivalent dose on the combination was 5.0 +/- 0.3 microg/kg/day in infants and 3.4 +/- 0.4 microg/kg/day in children above 2.5 years. Infants required higher liothyronine doses compared with older children (0.66 +/- 0.01 vs. 0.3 +/- 0.05 microg/kg/day). CONCLUSIONS: Combined therapy can achieve normal TSH levels with normal FT4 and FT3. Further long-term research is required to investigate effects on neurodevelopmental outcome.