Hereditary nonautoimmune hyperthyroidism is caused by activating germline mutations in the thyrotropin (TSH) receptor (TSHR) gene. We describe an extended Welsh kindred with toxic thyroid hyperplasia affecting 8 family members in three generations and a history consistent with thyrotoxicosis in a further three generations now deceased. A novel heterozygous germline mutation (ATG --> GTG; Met463Val) was identified in the second membrane spanning TSHR region in 6 relatives with thyrotoxicosis and goiter and absence of TSHR antibodies. Screening of 5 additional family members led to the identification of 2 siblings with the mutation, who were asymptomatic at the time, although subsequent thyroid function tests in these children showed suppressed serum TSH and increased serum free triiodothyronine (FT3) and free thyroxine (FT4) concentrations. Functional studies of the novel TSHR germline mutation demonstrated a constitutive activation of the cAMP pathway, which in the thyroid controls both thyroid hormone production and stimulation of thyroid growth. The molecular diagnosis in this family has clinical implications: genetic counseling is required, and primary thyroid ablation should be advocated as the preferred treatment in the patients with the constitutively activating TSHR germline mutation.

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ObjectiveTo determine the effect of prescription opioid use in the year before surgery on opioid consumption after surgery.BackgroundRecently developed postoperative opioid prescribing guidelines rely on data from opioid-naïve patients. However, opioid use in the USA is common, and the impact of prior opioid exposure on the consumption of opioids after surgery is unclear.MethodsPopulation-based cohort study of 26,001 adults 18 years of age and older who underwent one of nine elective general or gynecologic surgical procedures between January 1, 2017 and October 31, 2019, with prospectively collected patient-reported data from the Michigan Surgical Quality Collaborative (MSQC) linked to state prescription drug monitoring program at 70 MSQC-participating hospitals on 30-day patient-reported opioid consumption in oral morphine equivalents (OME) (primary outcome).ResultsCompared with opioid-naïve participants, opioid-exposed participants (26% of sample) consumed more prescription opioids after surgery (adjusted OME difference 12, 95% CI 10 to 14). Greater opioid exposure was associated with higher postoperative consumption in a dose-dependent manner, with chronic users reporting the greatest consumption (additional OMEs 32, 95% CI 21 to 42). However, for eight of nine procedures, 90% of opioid-exposed participants consumed ≤150 OMEs. Among those receiving perioperative prescriptions, opioid-exposed participants had higher likelihood of refill (adjusted OR 4.7, 95% CI 4.4 to 5.1), number of refills (adjusted incidence rate ratio 4.0, 95% CI 3.7 to 4.3), and average refill amount (adjusted OME difference 333, 95% CI 292 to 374)).ConclusionsPreoperative opioid use is associated with small increases in patient-reported opioid consumption after surgery for most patients, though greater differences exist for patients with chronic use. For most patients with preoperative opioid exposure, existing guidelines may meet their postoperative needs. However, guidelines may need tailoring for patients with chronic use, and providers should anticipate a higher likelihood of postoperative refills for all opioid-exposed patients.

Germline mutations in thyroid transcription factor 2 (TTF2) cause thyroid agenesis, spiky hair, and cleft palate, indicating thyroidal and extrathyroidal expression. We sought to investigate this by producing and applying an antibody to human TTF2. The coding region of human TTF2 was cloned into a bacterial expression vector, production of the soluble TTF2 protein optimized, and pure TTF2 obtained by nickel chromatography. Rabbits were immunized and the resulting TTF2 polyclonal titrated on formalin-fixed, paraffin-embedded sections of thyroid. The optimized protocol was applied to a range of tissues. Nine milligrams of TTF2 protein was obtained per liter of culture and a high-titer antibody produced. This displayed specific staining of thyroid follicular cell nuclei/cytoplasm and not of the interstitium, connective tissue, smooth muscle, or endothelium. No staining was obtained with the preimmune serum in the same conditions, or with the majority of other tissues tested with the TTF2 polyclonal. The exceptions were testis and skin, in which nuclear TTF2 immunoreactivity was present in the seminiferous tubules and cells in the follicular outer root sheath, respectively. In conclusion, we have produced a polyclonal antibody for human TTF2 and demonstrated immunoreactivity for this transcription factor in adult human thyroid and hair follicles and prepubertal testis.