Chromosome 9 alterations are the most frequently encountered cytologic anomalies in urothelial carcinoma (UC). We previously screened 139 low-stage UCs for loss of heterozygosity on chromosome 9, and identified five distinct regions likely to harbour tumour-suppressor genes. The present study focused on deletion mapping in the 9q22 region with 11 additional microsatellite markers. New deletions in the 9q22 region were found in five tumours. Deletion mapping allowed us to identify a 0.5 CM common minimal region of deletion between markers D9S280 and D9S1809, encompassing PATCHED (PTC), a gene identified as a tumour suppressor in basal cell carcinoma and in medulloblastoma. A marker located in the first intron of this gene showed the highest percentage of deletion (45%). cDNA sequencing in 15 tumours with deletion of PTC showed no mutation in the remaining allele. However, average expression of PTC mRNA measured by semiquantitative RT-PCR was significantly decreased in tumours with LOH in the 9q22 region, compared to normal urothelium (P ¼ 0.04), while it showed marked fluctuations in tumours without deletion. Our results suggest that the PTC gene is a putative suppressor at the 9q22 locus and that haploinsufficiency of this gene may be an early event in the development of papillary bladder tumours.

Objective To determine whether vitamin D3 supplementation improves insulin sensitivity, using the hyperinsulinemic-euglycemic clamp. Design This single-centre, double-blind, placebo-controlled trial randomised 96 participants at high risk of diabetes or with newly diagnosed type 2 diabetes to vitamin D3 5000 IU daily or placebo for 6 months. Methods We assessed at baseline and 6 months: (1) primary aim: peripheral insulin sensitivity (M-value using a 2-h hyperinsulinemic-euglycemic clamp); (2) secondary aims: other insulin sensitivity (HOMA2%S, Matsuda) and insulin secretion (insulinogenic index, C-peptide area under the curve, HOMA2-B) indices using a 2-h oral glucose tolerance test (OGTT); β-cell function (disposition index: M-value × insulinogenic index); fasting and 2-h glucose post OGTT; HbA1c; anthropometry. Results Baseline characteristics were similar between groups (% or mean ± s.d.): women 38.5%; age 58.7 ± 9.4 years; BMI 32.2 ± 4.1 kg/m2; prediabetes 35.8%; diabetes 20.0%; 25-hydroxyvitamin D (25(OH)D) 51.1 ± 14.2 nmol/L. At 6 months, mean 25(OH)D reached 127.6 ± 26.3 nmol/L and 51.8 ± 16.5 nmol/L in the treatment and placebo groups, respectively (P < 0.001). A beneficial effect of vitamin D3 compared with placebo was observed on M-value (mean change (95% CI): 0.92 (0.24–1.59) vs −0.03 (−0.73 to 0.67); P = 0.009) and disposition index (mean change (95% CI): 267.0 (−343.4 to 877.4) vs −55.5 (−696.3 to 585.3); P = 0.039) after 6 months. No effect was seen on other outcomes. Conclusions In individuals at high risk of diabetes or with newly diagnosed type 2 diabetes, vitamin D supplementation for 6 months significantly increased peripheral insulin sensitivity and β-cell function, suggesting that it may slow metabolic deterioration in this population.

The effects of anabolic implants, growth phase (growing vs finishing) and rate of growth on the priorities for protein and fat deposition were determined in yearling cattle. Santa Gertrudis crossbred yearling steers weighing 290 kg were individually fed diets varying in forage and grain content and either not implanted (n = 16) or implanted (90-d intervals) with Ralgro (n = 13) or Synovex-S (n = 12) implants. The cattle were fed toward a similar expected final empty BW (455 kg). Initial and interim empty body composition was measured via deuterium oxide dilution; final composition was determined by carcass specific gravity. During a 100-d growing phase, rates of protein gain were increased (P less than .12) to 118 and 131 g/d from 98 g/d for Ralgro and Synovex vs nonimplanted cattle, respectively. Concurrently, the fraction of protein in empty body growth was increased (P less than .09) from 17.5% for controls to 23.8 and 19.7% for Ralgro- and Synovex-implanted steers, respectively. This change in protein growth occurred concomitant with mobilization of fat and a reduction (P less than .04) in fat gain with Ralgro and Synovex implants. During the 136-d finishing phase, protein accretion was 115 and 132 vs 93 g/d for Ralgro- and Synovex-implanted cattle vs nonimplanted cattle; this represented a 24 and 42% increase (P less than .03) with Ralgro and Synovex, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

ObjectiveTo evaluate the effect of levothyroxine therapy on pregnancy outcomes compared with placebo or no treatment in women without overt hypothyroidism with presence of thyroid peroxidase antibodies (TPOAb) and/or thyroglobulin antibodies (TgAb).DesignSystematic review and meta-analysis of randomised controlled trialsStudy eligibility criteriaPrespecified criteria for inclusion were: randomised trials of levothyroxine versus control (placebo or no treatment) among women with positive TPOAb or TgAb who were pregnant or considering conception.Data sourcesOvid MEDLINE, EMBASE, CINAHL, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials were searched from 1980 to 5 November 2020.Outcome measuresPrespecified data elements were extracted and where appropriate, meta-analyses were conducted. Main outcomes include pregnancy achieved, miscarriage, preterm delivery and live birth.Risk of bias assessmentCochrane Risk of Bias Tool for Quality Assessment of Randomised Controlled Trials.ResultsFrom 3023 citations, 79 citations were identified for full-text review. Of these, six trials (total of 2263 women) were included for qualitative and quantitative analyses. Risk of bias was deemed low for only one trial. There was no significant difference in the relative risk (RR) of pregnancy achieved (RR 1.03; 95% CI 0.93 to 1.13), miscarriage (RR 0.93; 95% CI 0.76 to 1.14), preterm delivery (RR 0.66; 95% CI 0.39 to 1.10) or live births (RR 1.01; 95% CI 0.89 to 1.16) in thyroid autoimmune women treated with levothyroxine compared with controls. Sensitivity analyses of preterm birth identified study quality and timing of levothyroxine initiation as sources of heterogeneity.ConclusionsAmong pregnant women or women planning conception, with thyroid autoimmunity, there is a lack of evidence of benefit for levothyroxine use (moderate to high Grading of Recommendations, Assessment, Development and Evaluations). Recommendations to use levothyroxine in this setting need to be reconsidered.PROSPERO registration numberCRD42019130459.

Background: Women with hypothyroidism before pregnancy often require an increase in their levothyroxine dosage to maintain a euthyroid state during pregnancy. The objectives of this study were to investigate: (i) the frequency and distribution of thyrotropin (TSH) testing and levothyroxine dosage adjustment by gestational age, (ii) the magnitude of levothyroxine increase by the underlying etiology of hypothyroidism, and (iii) the relationship of overtreatment or undertreatment during pregnancy with adverse pregnancy outcomes among women using thyroid replacement before pregnancy. Methods: A retrospective cohort study of pregnancies in women on thyroid replacement before pregnancy in Alberta, Canada, was performed. Women using thyroid replacement anytime during the two years before pregnancy who delivered between October 2014 and September 2017 were included. Delivery records, physician billing, and laboratory and pharmacy administrative data were linked. Outcomes included characteristics of TSH testing, levothyroxine dosing, and pregnancy outcomes. The frequency and gestational timing of TSH testing and levothyroxine adjustments were calculated. Multiple logistic regression was used to test whether pregnancies with TSH <0.10 mIU/L (overtreatment) or TSH ≥10.00 mIU/L (undertreatment) compared with control pregnancies (TSH 0.10–4.00 mIU/L) were associated with adverse pregnancy and neonatal outcomes. Results: Of the 10,680 deliveries, 8774 (82.2%) underwent TSH testing at least once during pregnancy, at a median gestational age of six weeks. An adjustment of levothyroxine dosage was made for 4321 (43.7%) during pregnancy. TSH in pregnancy below 0.10 mIU/L increased the odds of preterm delivery when compared with control pregnancies (adjusted odds ratio, 2.14 [95% confidence interval 1.51–2.78]). TSH ≥10.00 mIU/L during pregnancy was not associated with any adverse pregnancy or neonatal outcomes in the multivariable analysis. Conclusions: Although most women on thyroid replacement before conception had TSH measured at some point during pregnancy, it is concerning that 17.8% did not. Levothyroxine overtreatment in pregnancy was associated with preterm delivery. These findings suggest that clinicians should be careful to avoid overtreatment with levothyroxine in pregnancy.

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