Weight-based thyroid dosing vs fixed dosing during pregnancy for subclinical hypothyroidism: A retrospective cohort study.

OBJECTIVE: Thyroid hormones play a crucial role in foetal growth and neurocognitive development. Our aim was to compare a weight-based dosing method of starting thyroxine to a fixed-dose method in newly diagnosed women with subclinical hypothyroidism during pregnancy. DESIGN: We performed a retrospective cohort study of consecutive women with newly diagnosed subclinical hypothyroidism during pregnancy seen at Mount Sinai Hospital and Women's College Hospital, Toronto, Canada 2015-2018. PATIENTS: We identified women that were treated based on pre-pregnancy weight and those that were given a fixed dose of 50 mcg/day. MEASUREMENTS: The percent of women who reached the target TSH of <2.5 mIU/L within 4-8 weeks was compared using a chi-squared test and a logistic regression model, adjusting for age, initial TSH and gestational age treatment was started. RESULTS: 393 women were included: 252 treated using a fixed-dose approach; 141 treated based on pre-pregnancy weight. In the unadjusted analysis, there was no difference between the groups in the percentage of women in the target range within 4-8 weeks (89.6% in the fixed-dose group vs 88.8% in the weight-based group (p = .954)). However, after adjustment for between-group differences in age, initial TSH and gestational age treatment was started, there was a significantly greater odds of achieving the target range using the weight-based dosing (OR 4.26 (1.60-11.7), p = .004). CONCLUSIONS: Treating women with newly diagnosed subclinical hypothyroidism during pregnancy with a weight-based strategy increased the odds of reaching the target TSH range within 4-8 weeks. Clinicians caring for these women should consider this approach when starting treatment during pregnancy.

Chloride-liberal fluids are associated with acute kidney injury after liver transplantation.

INTRODUCTION: Acute kidney injury (AKI) occurs frequently after liver transplantation and is associated with significant morbidity and mortality. Recent evidence has linked the predominant usage of 'chloride-liberal' intravenous fluids, such as 0.9% saline to the development of renal dysfunction in general critically ill patients. We compared the effects of perioperative fluid types on AKI in liver transplant recipients. METHODS: An observational analysis of liver transplant recipients over a 33-month period, between January 2010 and September 2013, was performed. Intensive care unit database and patient records were analyzed for determinants of early postoperative AKI. Univariate and multivariate regression analysis was carried out using a two-tailed P value less than 0.05 to establish significance. The institutional Research Ethics Committee approved the study methodology (RAC no. 2131 073). RESULTS: One hundred and fifty-eight liver transplants were performed, AKI developed in 57 (36.1%) patients: 39 (68.4%) fully recovered, 13 (22.8%) developed chronic renal failure and 10 (17.5%) required long-term hemodialysis. On univariate regression analysis, AKI was significantly associated with greater than 3,200 ml of chloride-liberal fluids infused within the first postoperative day (HR 5.9, 95% CI 2.64, 13.2, P < 0.001), greater than 1,500 ml colloids received in the operating room (hazard ratio (HR) 1.97, 95% CI 1.01, 3.8, P = 0.046), vasopressor requirement for 48 hours posttransplant (HR 3.34, 95% CI 1.55, 7.21, P = 0.002), hyperchloremia at day 2 (HR 1.09, 95% CI 1.01, 1.18, P = 0.015) and preoperative model for end-stage liver disease (MELD) score (HR 1.08, 95% CI 1.03, 1.13, P < 0.001). After stepwise multivariate regression, infusion of greater than 3,200 ml of chloride-liberal fluids (HR 6.25, 95% CI 2.69, 14.5, P < 0.000) and preoperative MELD score (HR 1.08, 95% CI 1.02, 1.15, P = 0.004) remained significant predictors for AKI. CONCLUSIONS: In a sample of liver transplant recipients, infusion of higher volumes of chloride-liberal fluids and preoperative status was associated with an increased risk for postoperative AKI.

Patterns of neurological manifestations in Woodhouse-Sakati Syndrome.

BACKGROUND: Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive disease with characteristic neuro-endocrine manifestations. WSS encompasses heterogeneous phenotypes and disease course. OBJECTIVE: We aimed to characterize neurological involvement of the disease through subgrouping of core neurological manifestations. METHODS: A single-institution retrospective analysis of patients with clinically and genetically confirmed diagnosis of WSS. RESULTS: A total of 38 individuals belonging to 17 families were identified to have WSS. The mean age at enrollment was 30.1 years (range 16-53 years). Neurological involvement was noted in 31 patients (81.5%). Dystonia was the most common neurological manifestation (67%), followed by intellectual disability (45%) and sensorineural hearing loss (30%). Based on the Neurological Impairment Scale (NIS), the disease was recognized to have two distinct patterns. A disabling, rapidly progressive pattern (NIS of 3-4; Type 1) was noted in eighteen patients (12 males, 6 females; 47.4%) with severe disability that occurs within a mean duration of 7.4 ±â€¯3.6 years. Type 2 WSS was identified in twenty patients (8 males, 12 females; 52.6%), and showed either absent or mild neurological involvement with preserved activities of daily living (NIS of 0-1). The mean age of onset for neurological manifestations was earlier in type 1 (12.6 ±â€¯4.5 years) compared to type 2 (18.1 ±â€¯4.3 years). Type 1 WSS has a significantly higher rate of intellectual disability (p= <0.001). CONCLUSIONS: In this pleiotropic syndrome, we identified two distinct phenotypes with variable prognosis. A high Interfamilial and intrafamilial phenotypic variability despite having a similar gene mutation suggests a possible role of genetic or environmental modifying factor.

Autosomal recessive ADCY5-Related dystonia and myoclonus: Expanding the genetic spectrum of ADCY5-Related movement disorders.

INTRODUCTION: ADCY5-related hyperkinesia encompasses a heterogeneous group of phenotypes, including paroxysmal chorea, myoclonus, and dystonia. The disease is attributed to mutations of ADCY5, which encodes an adenylate cyclase enzyme. The disease can occur in a sporadic or familial pattern. With exception of one study, all reports on familial ADCY5-related hyperkinesia were associated with an autosomal dominant inheritance. Herein, we describe a native Arabian Bedouin family with an autosomal recessive ADCY5-related disorder and expand the genotypic and phenotypic spectrum of this disorder. METHODS: The pedigree included 4 generations of a family with 6 affected individuals. The patients were examined clinically and radiologically. Homozygosity mapping and Whole Exome Sequencing (WES) were used to identify a variant, predicted to be pathogenic, which segregated with disease in this family. RESULTS: All patients presented with early-onset dystonia and myoclonus. The patients had delayed motor and language milestones, axial hypotonia, severe anxiety, social phobia, and isolation. One patient had dilated cardiomyopathy. WES of one affected individual revealed a novel homozygous missense mutation (c.1762G > A, p.D588N) of ADCY5, that segregated with disease in an autosomal recessive manner, and was absent in more than 1000 ethnically-matched chromosomes. The mutation replaces a highly conserved nucleotide and is predicted to be deleterious. CONCLUSION: This study reports the second family with autosomal recessive childhood-onset ADCY5-related disorder and expands our understanding of phenotype/genotype correlations of this disorder.