Conservative management versus tonsillectomy in adults with recurrent acute tonsillitis in the UK (NATTINA): a multicentre, open-label, randomised controlled trial

Background: Tonsillectomy is regularly performed in adults with acute tonsillitis, but with scarce evidence. A reduction in tonsillectomies has coincided with an increase in acute adult hospitalisation for tonsillitis complications. We aimed to assess the clinical effectiveness and cost-effectiveness of conservative management versus tonsillectomy in patients with recurrent acute tonsillitis. Methods: This pragmatic multicentre, open-label, randomised controlled trial was conducted in 27 hospitals in the UK. Participants were adults aged 16 years or older who were newly referred to secondary care otolaryngology clinics with recurrent acute tonsillitis. Patients were randomly assigned (1:1) to receive tonsillectomy or conservative management using random permuted blocks of variable length. Stratification by recruiting centre and baseline symptom severity was assessed using the Tonsil Outcome Inventory-14 score (categories defined as mild 0–35, moderate 36–48, or severe 49–70). Participants in the tonsillectomy group received elective surgery to dissect the palatine tonsils within 8 weeks after random assignment and those in the conservative management group received standard non-surgical care during 24 months. The primary outcome was the number of sore throat days collected during 24 months after random assignment, reported once per week with a text message. The primary analysis was done in the intention-to-treat (ITT) population. This study is registered with the ISRCTN registry, 55284102. Findings: Between May 11, 2015, and April 30, 2018, 4165 participants with recurrent acute tonsillitis were assessed for eligibility and 3712 were excluded. 453 eligible participants were randomly assigned (233 in the immediate tonsillectomy group vs 220 in the conservative management group). 429 (95%) patients were included in the primary ITT analysis (224 vs 205). The median age of participants was 23 years (IQR 19–30), with 355 (78%) females and 97 (21%) males. Most participants were White (407 [90%]). Participants in the immediate tonsillectomy group had fewer days of sore throat during 24 months than those in the conservative management group (median 23 days [IQR 11–46] vs 30 days [14–65]). After adjustment for site and baseline severity, the incident rate ratio of total sore throat days in the immediate tonsillectomy group (n=224) compared with the conservative management group (n=205) was 0·53 (95% CI 0·43 to 0·65; <0·0001). 191 adverse events in 90 (39%) of 231 participants were deemed related to tonsillectomy. The most common adverse event was bleeding (54 events in 44 [19%] participants). No deaths occurred during the study. Interpretation: Compared with conservative management, immediate tonsillectomy is clinically effective and cost-effective in adults with recurrent acute tonsillitis. Funding: National Institute for Health Research

Glucose-6-phosphate-mediated activation of liver glycogen synthase plays a key role in hepatic glycogen synthesis

The liver responds to an increase in blood glucose levels in the postprandial state by uptake of glucose and conversion to glycogen. Liver glycogen synthase (GYS2), a key enzyme in glycogen synthesis, is controlled by a complex interplay between the allosteric activator glucose-6-phosphate (G6P) and reversible phosphorylation through glycogen synthase kinase-3 and the glycogen-associated form of protein phosphatase 1. Here, we initially performed mutagenesis analysis and identified a key residue (Arg(582)) required for activation of GYS2 by G6P. We then used GYS2 Arg(582)Ala knockin (+/R582A) mice in which G6P-mediated GYS2 activation had been profoundly impaired (60–70%), while sparing regulation through reversible phosphorylation. R582A mutant–expressing hepatocytes showed significantly reduced glycogen synthesis with glucose and insulin or glucokinase activator, which resulted in channeling glucose/G6P toward glycolysis and lipid synthesis. GYS2(+/R582A) mice were modestly glucose intolerant and displayed significantly reduced glycogen accumulation with feeding or glucose load in vivo. These data show that G6P-mediated activation of GYS2 plays a key role in controlling glycogen synthesis and hepatic glucose-G6P flux control and thus whole-body glucose homeostasis