Switching to once-weekly insulin icodec versus once-daily insulin glargine U100 in individuals with basal-bolus insulin-treated type 2 diabetes (ONWARDS 4): a phase 3a, randomised, open-label, multicentre, treat-to-target, non-inferiority trial.

BACKGROUND: Insulin icodec (icodec) is a basal insulin analogue suitable for once-weekly dosing. ONWARDS 4 aimed to assess the efficacy and safety of once-weekly icodec compared with once-daily insulin glargine U100 (glargine U100) in individuals with long-standing type 2 diabetes on a basal-bolus regimen. METHODS: In this 26-week, phase 3a, randomised, open-label, multicentre, treat-to-target, non-inferiority trial, adults from 80 sites (outpatient clinics and hospital departments) across nine countries (Belgium, India, Italy, Japan, Mexico, the Netherlands, Romania, Russia, and the USA) with type 2 diabetes (glycated haemoglobin [HbA1c] 7·0-10·0%) were randomly assigned (1:1) to receive once-weekly icodec or once-daily glargine U100 combined with 2-4 daily bolus insulin aspart injections. The primary outcome was change in HbA1c from baseline to week 26 (non-inferiority margin of 0·3 percentage points). The primary outcome was evaluated in the full analysis set (ie, all randomly assigned participants). Safety outcomes were evaluated in the safety analysis set (ie, all participants randomly assigned who received at least one dose of trial product). This trial is registered with ClinicalTrials.gov, NCT04880850. FINDINGS: Between May 14 and Oct 29, 2021, 746 participants were screened for eligibility, of whom 582 (78%) were randomly assigned (291 [50%] to icodec treatment and 291 [50%] to glargine U100 treatment). Participants had a mean duration of type 2 diabetes of 17·1 years (SD 8·4). At week 26, estimated mean change in HbA1c was -1·16 percentage points in the icodec group (baseline 8·29%) and -1·18 percentage points in the glargine U100 group (baseline 8·31%), showing non-inferiority for icodec versus glargine U100 (estimated treatment difference 0·02 percentage points [95% CI -0·11 to 0·15], p<0·0001). Overall, 171 (59%) of 291 participants in the icodec group and 167 (57%) of 291 participants in the glargine U100 group had an adverse event. 35 serious adverse events were reported in 22 (8%) of 291 participants in the icodec group and 33 serious adverse events were reported in 25 (9%) of 291 participants receiving glargine U100. Overall, combined level 2 and level 3 hypoglycaemia rates were similar between treatment groups. No new safety concerns were identified for icodec. INTERPRETATION: In people with long-standing type 2 diabetes on a basal-bolus regimen, once-weekly icodec showed similar improvements in glycaemic control, with fewer basal insulin injections, lower bolus insulin dose, and with no increase in hypoglycaemic rates compared with once-daily glargine U100. Key strengths of this trial include the use of masked continous glucose monitoring; the high trial completion rate; and the inclusion of a large, diverse, and multinational population. Limitations include the relatively short trial duration and the open-label design. FUNDING: Novo Nordisk.

Rising cost of insulin: A deterrent to compliance in patients with diabetes mellitus.

BACKGROUND AND AIMS: The rapid increase in burden of type 2 diabetes mellitus (T2DM), poses a huge medico-economic challenge, especially when the cost of care is funded by out-of-pocket expenses. The aim of this review is to highlight various issues associated with rising cost of insulin, prevalence of cost-related insulin underuse, insulin related cost-saving behaviors, and viable solutions for the benefit of patients with T2DM receiving insulin. METHODS: Electronic databases (PubMed and Google Scholar) from 2000 to 2020 were searched using the key terms uncontrolled diabetes mellitus, insulin therapy, glycemic control, direct cost, indirect cost, out-of-pocket expenses, cost-related insulin underuse, cost-saving behaviors, and biosimilar insulin in developed countries and India. RESULTS: In majority of the patients with T2DM on monotherapy, addition of another oral antidiabetic agent is required. Despite these measures, the target glycemic goals are not achieved in majority of the patients resulting in various complications. These complications can be prevented and target glycemic goals can be achieved with early initiation of insulin therapy. However, rising cost is a major deterrent to the lifelong use of insulin. This results in non-compliance and further deterioration of glycemic control. Recently, biosimilar insulins have revolutionized the management of T2DM and look promising from the economic point of view. CONCLUSIONS: Biosimilar insulins are likely to further enhance the compliance of patients and should be used whenever feasible in patients with DM. However, the patient, along with prescriber should be allowed to make shared, informed decisions regarding the insulin they wish to use.

Utility of Non-EPI DWI MRI Imaging in Cholesteatoma: The Indian Perspective.

The purpose of this prospective observational study was to evaluate the diagnostic performance of non-EPI-based techniques, in detecting both primary and residual/recurrent cholesteatoma in a tertiary care center. 56 patients (25 female and 31 male) aged between 6 and 59 years were prospectively evaluated for the presence or absence of cholesteatoma. This included both primary and postoperative recurrent cholesteatoma (16). All the patients underwent sequential CT scans of temporal bones and non-EPI DWI (Non-Echo Planar Diffusion-Weighted Imaging) MRI techniques. The findings were correlated with surgical findings regarding the presence or absence of cholesteatoma. The size of cholesteatoma that was diagnosed on non-EPI DWI MRI was measured. The smallest size was 6 mm and the largest one was 21 mm. The accuracy of non-EPI DWI MRI in diagnosing cholesteatoma (primary and recurrent) was 97.5%. Whereas in diagnosing recurrent cholesteatoma accuracy was 100%. Accuracy of non-EPI DWI MRI is very high in diagnosing cholesteatoma especially in recurrent cholesteatoma and can potentially replace second look surgery when intact canal wall techniques are used. The technique is best used with a CT Scan of the temporal bone to depict bony changes, anatomical variants, or complications. The combination of HRCT and non-EPI DWI needs to be employed in diagnosing primary and recurrent cholesteatoma to maximize the diagnostic benefit as they are complimentary.

Understanding Patients' Willingness to Pay for Biphasic Insulin Aspart 30/70 in a Pen Device for Type 2 Diabetes Treatment in an Out-of-Pocket Payment Market.

OBJECTIVE: Our objective was to investigate willingness to pay (WTP) for biphasic insulin aspart 30/70 (BIAsp 30) in patients with type 2 diabetes mellitus (T2DM) in India. METHODS: A multicenter, prospective, non-interventional, preference study was conducted that assessed WTP for BIAsp 30 in an insulin pen (FlexPen® or Penfill® device) in patients in India with T2DM previously treated with biphasic human insulin (BHI) in vials and believed to be able to pay for treatment. The primary endpoint was the proportion of patients willing to continue to pay for BIAsp 30 after 12 weeks' treatment. Secondary endpoints included the change from baseline in treatment and device satisfaction and patient preferences for treatment attributes as assessed by a nested discrete-choice experiment. RESULTS: Overall, 54.9% (n = 277/505) of participants were male; the mean age was 56.4 years; diabetes duration was 10.9 years; 63.8% had a body mass index ≥ 25 kg/m2; > 75% had an annual household income > 150,000 Indian rupees (INR). After 12 weeks' treatment, 96.4% of patients were willing to pay for BIAsp 30. Mean treatment and device satisfaction significantly improved from baseline (p < 0.0001). Patients were willing to pay INR3576 (95% confidence interval [CI] 2755-4398) for improved glycemic control, INR688 (95% CI 383-994) for a device upgrade (vial/syringe to an insulin pen), or INR327 (95% CI 95-560) to avoid major hypoglycemia. Patients would need to be compensated INR44 (95% CI 56-32) per minor hypoglycemic event. CONCLUSIONS: In India, patients with T2DM previously treated with BHI were willing to pay for BIAsp 30 in an insulin pen. Furthermore, treatment and device satisfaction improved after this therapeutic switch. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03374774.

Sialendoscopic Management of Obstructive Salivary Gland Pathology: A Retrospective Analysis of 236 Cases.

PURPOSE: To analyze and assess the results of treating obstructive salivary gland pathology by sialendoscopy or sialendoscopic-assisted surgery and analyze the difference in submandibular and parotid gland pathology. PATIENTS AND METHODS: Between December 2012 and March 2020, 211 patients (236 procedures) underwent sialendoscopy/sialendoscopic-assisted surgery for treatment of obstructive salivary gland pathology. The cases were retrospectively analyzed for type of pathology, symptomatic relief, type of intervention (endoscopy alone or combined with open surgery), recurrence of symptoms, number of gland excisions, and complications encountered. Sialolith cases (n = 117) were treated by sialendoscopic/sialendoscopy-assisted surgical sialolithotomy using basket or graspers. Strictures (n = 69) were treated by serial dilatation or balloon dilatation with or without intraductal steroid. Mucous plugs (n = 26) were managed by sialendoscopic lavage and occasional retrieval using wire baskets. RESULTS: There were 123 submandibular sialendoscopies in 118 patients and 113 parotid sialendoscopies in 95 patients. Of the 123 submandibular sialendoscopies, 99 were treated for sialolithiasis, 14 for strictures, 3 for mucous plugs, and 2 for foreign bodies. Of the 95 parotid sialendoscopies, 18 were treated for sialolithiasis, 55 for strictures, 23 for mucous plugs, and 1 for foreign body. The success rate was 85.3% for submandibular gland treatment and 92% for parotid gland treatment. About 62.7% of cases were treated by combined method (sialendoscopy with open approach) in submandibular gland and 50% in parotid gland. The number of gland excisions performed was 5 (2.1%). CONCLUSIONS: Sialendoscopy although associated with a gradual learning curve can be used for all cases of obstructive salivary gland pathology with excellent success rate and minimum morbidity. Parotid gland obstructive pathology is distinct from that seen in the submandibular gland, with strictures and mucous plugs contributing to most cases. Diagnosing and treatment planning for strictures and mucous plugs should therefore be as seamless as that for sialoliths.

Efficacy of Ribbond and a fibre post on the fracture resistance of reattached maxillary central incisors with two fracture patterns: a comparative in vitro study.

AIM: To compare the fracture resistance of maxillary central incisor fragments having two different fracture patterns and re-attached using two different posts - fibre post and Ribbond. MATERIALS AND METHODS: Sixty extracted human maxillary central incisors were randomly divided into two groups of thirty samples each. Group A consisted of samples with 'labio-palatal' fracture pattern and Group B with a 'palato-labial' fracture pattern. The crowns of all the samples were sectioned using safe-sided diamond discs. Following cleaning and shaping and sectional obturation, the samples were randomly subdivided into two subgroups of 15 samples each. Prefabricated fibre post (Reforpost, Angelus, Londrina, PR, Brazil) was placed in all samples of Subgroup I, and Ribbond (Ribbond Inc., Seattle, WA, USA) was placed in all samples of Subgroup II. The fragments were re-attached, fracture resistance was tested using Instron Universal Testing Machine, and the failure modes were assessed using a stereomicroscope. RESULTS: Group A with a labio-palatal fracture pattern exhibited higher fracture resistance as compared to Group B (palato-labial) in both subgroups. The fibre post (Subgroup I) exhibited higher fracture resistance as compared to Ribbond (Subgroup II). The Ribbond group exhibited significantly more number of repairable failures as compared to fibre post group. CONCLUSION: The labio-palatal pattern of fracture is a favourable type of fracture on palatal load application. The fragments re-attached using the fibre post (Reforpost) had a higher resistance to fracture. However, teeth restored with Ribbond posts exhibited 100% repairable failures upon load application. The fracture pattern had no influence on the failure modes.

Identification and characterization of a virus-inducible non-coding RNA in mouse brain.

Infection of mice with Japanese encephalitis virus or Rabies virus results in the activation of a gene encoding a novel, non-coding RNA (ncRNA) in the mouse central nervous system. This transcript, named virus-inducible ncRNA (VINC), is identical to a 3.18 kb transcript expressed in mouse neonate skin (GenBank accession no. AK028745) that, together with a number of unannotated cDNAs and expressed sequence tags, is grouped in the mouse unigene cluster Mm281895. VINC is expressed constitutively in early mouse embryo and several adult non-neuronal mouse tissues, as well as a murine renal adenocarcinoma (RAG) cell line. Northern blotting of nuclear and cytoplasmic RNAs revealed that VINC is localized primarily in the nucleus of RAG cells and is thus a novel member of the nuclear ncRNA family.

Ectopic thyroid: A rare cause of tracheal obstruction.

The endoluminal presence of thyroid tissue in the trachea is a rare cause of airway obstruction. Only 14 well documented cases of intratracheal ectopic thyroid tissue have been reported in English Literature since 1966. These lesions are mostly benign and nearly all patients present with symptoms of respiratory obstruction. We present a case of ectopic thyroid in cervical trachea presenting with symptoms of airway obstruction. Thorough clinical examination and investigations were carried out. A right hemithyroidectomy and excision of a part of the tracheal wall through a tracheotomy was performed for removal of the ectopic thyroid tissue from trachea. The clinicians & radiologists must be aware of this entity to avoid mistaking it for evidence of invasion by a malignant neoplas, and hence this report.