Inconsistent Provider Testing Practices for Congenital Cytomegalovirus: Missed Diagnoses and Missed Opportunities.

Newborn congenital cytomegalovirus (cCMV) screening programs have been found to increase the rates of early diagnosis and treatment. In North America, newborn cCMV screening programs have not been widely implemented, leaving healthcare providers to rely on clinical suspicion alone to prompt testing. This study sought to examine healthcare providers' cCMV testing practices at a quaternary children's hospital. A retrospective review of the electronic health record was completed for eligible infants over a six-year period. Bivariate calculations and analyses were performed. Between 2014 and 2019, a total of 40,091 infants were cared for at the study institution, of which 178 were tested for cCMV and 10 infants were diagnosed with cCMV. Isolated small-for-gestational age was the most common indication (53/178) to prompt testing. Overall, the cCMV testing rate was 4.5 tests per 1000 infants, with a resulting diagnostic prevalence of 0.2 cases per 1000 infants, which is 15-fold lower than the expected prevalence. Providers relying on clinical suspicion alone are infrequently testing infants for cCMV, resulting in missed diagnoses and missed opportunities for treatment. Systematic cCMV screening practices may improve diagnosis, treatment, and childhood outcomes.

Understanding Worry About Risks Associated With Thyroid Hormone Therapy: A National Survey of Endocrinologists, Family Physicians, and Geriatricians.

OBJECTIVE: Thyroid hormone use is widespread, and prior studies have shown that over- and undertreatment with thyroid hormone are common. Our objective was to understand physician worry regarding risks associated with thyroid hormone therapy, specifically overtreatment or undertreatment. METHODS: A nationwide survey was administered to physician members of the Endocrine Society, the American Academy of Family Practice, and the American Geriatrics Society. Participants were asked how often they were worried about various risks that may be associated with thyroid hormone over- or undertreatment, that is, cardiovascular complications, bone complications, and poor quality of life due to overtreatment or undertreatment with thyroid hormone. Multivariable regression analyses were conducted to determine physician characteristics associated with each worry. RESULTS: The response rate was 63% (359 of 566); of those who responded, 128 (36%) were primary care physicians, 114 (32%) were endocrinologists, and 113 (32%) were geriatricians. Overall, 74 (21%) physicians reported that they frequently or always worried about cardiovascular complications, 74 (21%) about bone complications, 111 (31%) about the poor quality of life due to symptoms from undertreatment with thyroid hormone, and 87 (24%) about the poor quality of life due to symptoms from overtreatment with thyroid hormone. Endocrinologists were more likely to frequently or always worry about the patients' poor quality of life due to symptoms from overtreatment (odds ratio, 2.05; 95% confidence interval, 1.09-3.93) compared with primary care physicians. CONCLUSION: Up to one third of the physicians frequently or always worried about risks resulting from the thyroid hormone overtreatment or undertreatment. More research is needed across specialties to understand physician perceptions of how thyroid hormone therapy impacts the patients' quality of life.

Identification of the leptin receptor sequences crucial for the STAT3-Independent control of metabolism.

BACKGROUND: Leptin acts via its receptor, LepRb, on specialized neurons in the brain to modulate energy balance and glucose homeostasis. LepRb→STAT3 signaling plays a crucial role in leptin action, but LepRb also mediates an additional as-yet-unidentified signal (Signal 2) that is important for leptin action. Signal 2 requires LepRb regions in addition to those required for JAK2 activation but operates independently of STAT3 and LepRb phosphorylation sites. METHODS: To identify LepRb sequences that mediate Signal 2, we used CRISPR/Cas9 to generate five novel mouse lines containing COOH-terminal truncation mutants of LepRb. We analyzed the metabolic phenotype and measures of hypothalamic function for these mouse lines. RESULTS: We found that deletion of LepRb sequences between residues 921 and 960 dramatically worsens metabolic control and alters hypothalamic function relative to smaller truncations. We also found that deletion of the regions including residues 1013-1053 and 960-1013 each decreased obesity compared to deletions that included additional COOH-terminal residues. CONCLUSIONS: LepRb sequences between residues 921 and 960 mediate the STAT3 and LepRb phosphorylation-independent second signal that contributes to the control of energy balance and metabolism by leptin/LepRb. In addition to confirming the inhibitory role of the region (residues 961-1013) containing Tyr985, we also identified the region containing residues 1013-1053 (which contains no Tyr residues) as a second potential mediator of LepRb inhibition. Thus, the intracellular domain of LepRb mediates multiple Tyr-independent signals.

Defining the Transcriptional Targets of Leptin Reveals a Role for Atf3 in Leptin Action.

Leptin acts via its receptor (LepRb) to modulate gene expression in hypothalamic LepRb-expressing neurons, thereby controlling energy balance and glucose homeostasis. Despite the importance of the control of gene expression in hypothalamic LepRb neurons for leptin action, the transcriptional targets of LepRb signaling have remained undefined because LepRb cells contribute a small fraction to the aggregate transcriptome of the brain regions in which they reside. We thus employed translating ribosome affinity purification followed by RNA sequencing to isolate and analyze mRNA from the hypothalamic LepRb neurons of wild-type or leptin-deficient (Lepob/ob) mice treated with vehicle or exogenous leptin. Although the expression of most of the genes encoding the neuropeptides commonly considered to represent the main targets of leptin action were altered only following chronic leptin deprivation, our analysis revealed other transcripts that were coordinately regulated by leptin under multiple treatment conditions. Among these, acute leptin treatment increased expression of the transcription factor Atf3 in LepRb neurons. Furthermore, ablation of Atf3 from LepRb neurons (Atf3LepRbKO mice) decreased leptin efficacy and promoted positive energy balance in mice. Thus, this analysis revealed the gene targets of leptin action, including Atf3, which represents a cellular mediator of leptin action.