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Research methodology This case was developed from both primary and secondary sources. Primary sources were interviews. The secondary sources include legal opinions and journal articles. Case overview/synopsis In 2012, Scot and his co-owner, both experienced groomers, planned to open their own grooming business. Scott talked with his accountant about the best legal entity for their situation, and the accountant advised Scott that a limited liability company (LLC) would be the best choice. The accountant steered Scott to Legal Zoom, an online legal resource that helps people form business entities, including LLCs. A few years after starting their business, Scott and his co-owner reached an impasse: Scott wanted to expand the business; his co-owner did not. Scott talked with an attorney and learned that the standard form LLC operating agreement from Legal Zoom did not cover this kind of situation. How is an LLC formed? What are the consequences of a flawed LLC formation? What kinds of duties do accountants owe business owners? Complexity academic level This case was written for use in an undergraduate introductory business law course, an introductory accounting course or an accounting ethics course. The focus of the case supports classroom discussion for online and face-to-face instruction regarding business entity formation and fiduciary duties. Educators who use critical thinking in lessons to apply information about the roles of accountants and attorneys working with business owners can use this case to explore and discuss the impact ethical decisions can have on business owner clients. Learning objectives Through evaluating and examining this case, students will be able to: • understand what an LLC is and explain how one is formed; • recognize the consequences of flawed LLC business entity formation; and • articulate the roles of accountants in the formation of an LLC.

OBJECTIVE To explore the effect of discontinuing continuous glucose monitoring (CGM) after 8 months of CGM use in adults with type 2 diabetes treated with basal without bolus insulin. RESEARCH DESIGN AND METHODS This multicenter trial had an initial randomization to either real-time CGM or blood glucose monitoring (BGM) for 8 months followed by 6 months in which the BGM group continued to use BGM (n = 57) and the CGM group was randomly reassigned either to continue CGM (n = 53) or discontinue CGM with resumption of BGM for glucose monitoring (n = 53). RESULTS In the group that discontinued CGM, mean time in range (TIR) 70–180 mg/dL, which improved from 38% before initiating CGM to 62% after 8 months of CGM, decreased after discontinuing CGM to 50% at 14 months (mean change from 8 to 14 months −12% [95% CI −21% to −3%], P = 0.01). In the group that continued CGM use, little change was found in TIR from 8 to 14 months (baseline 44%, 8 months 56%, 14 months 57%, mean change from 8 to 14 months 1% [95% CI −11% to 12%], P = 0.89). Comparing the two groups at 14 months, the adjusted treatment group difference in mean TIR was −6% (95% CI −16% to 4%, P = 0.20). CONCLUSIONS In adults with type 2 diabetes treated with basal insulin who had been using real-time CGM for 8 months, discontinuing CGM resulted in a loss of about one-half of the initial gain in TIR that had been achieved during CGM use.

Objective: To explore the effect of discontinuing continuous glucose monitoring (CGM) after 8 months of CGM use in adults with type 2 diabetes treated with basal without bolus insulin. Research Design and Methods: Multi-center trial with an initial randomization to either real-time CGM or blood glucose monitoring (BGM) for 8 months, followed by 6 months in which the BGM Group continued to use BGM (N=57) and the CGM Group was re-randomized either to continue CGM (N=53) or discontinue CGM with resumption of BGM for glucose monitoring (N=53). Results: In the group that discontinued CGM, mean time in range 70-180 mg/dL (TIR), which improved from 38% prior to initiating CGM to 62% after 8 months of CGM, decreased after discontinuing CGM to 50% at 14 months (mean change from 8 to 14 months = -12%, 95% CI -21% to -3%, P=0.01). In the group continuing CGM, there was little change in TIR from 8 to 14 months (baseline 44%, 8 months 56%, 14 months 57%; mean change 8 to 14 months = 1%, 95% CI -11% to 12%, P=0.89). Comparing the two groups at 14 months, the adjusted treatment group difference in mean TIR was -6% (95% CI -16% to 4%, P=0.20). Conclusions: In adults with type 2 diabetes treated with basal insulin who had been using real-time CGM for 8 months, discontinuing CGM resulted in a loss of about half of the initial gain in TIR that had been achieved during CGM use.

IMPORTANCE: Continuous glucose monitoring (CGM) has been shown to be beneficial for adults with type 2 diabetes using intensive insulin therapy, but its use in type 2 diabetes treated with basal insulin without prandial insulin has not been well studied. OBJECTIVE: To determine the effectiveness of CGM in adults with type 2 diabetes treated with basal insulin without prandial insulin in primary care practices. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial was conducted at 15 centers in the US (enrollment from July 30, 2018, to October 30, 2019; follow-up completed July 7, 2020) and included adults with type 2 diabetes receiving their diabetes care from a primary care clinician and treated with 1 or 2 daily injections of long- or intermediate-acting basal insulin without prandial insulin, with or without noninsulin glucose-lowering medications. INTERVENTIONS: Random assignment 2:1 to CGM (n = 116) or traditional blood glucose meter (BGM) monitoring (n = 59). MAIN OUTCOMES AND MEASURES: The primary outcome was hemoglobin A(1c) (HbA(1c)) level at 8 months. Key secondary outcomes were CGM-measured time in target glucose range of 70 to 180 mg/dL, time with glucose level at greater than 250 mg/dL, and mean glucose level at 8 months. RESULTS: Among 175 randomized participants (mean [SD] age, 57 [9] years; 88 women [50%]; 92 racial/ethnic minority individuals [53%]; mean [SD] baseline HbA(1c) level, 9.1% [0.9%]), 165 (94%) completed the trial. Mean HbA(1c) level decreased from 9.1% at baseline to 8.0% at 8 months in the CGM group and from 9.0% to 8.4% in the BGM group (adjusted difference, −0.4% [95% CI, −0.8% to −0.1%]; P = .02). In the CGM group, compared with the BGM group, the mean percentage of CGM-measured time in the target glucose range of 70 to 180 mg/dL was 59% vs 43% (adjusted difference, 15% [95% CI, 8% to 23%]; P

Background Dapagliflozin is a sodium-glucose cotransporter-2 inhibitor approved for the treatment of type 2 diabetes. We aimed to assess the efficacy and safety of dapagliflozin as an add-on to adjustable insulin in patients with inadequately controlled type 1 diabetes. Methods DEPICT-1 was a double-blind, randomised, parallel-controlled, three-arm, phase 3, multicentre study done at 143 sites in 17 countries. Eligible patients were aged 18–75 years and had inadequately controlled type 1 diabetes (HbA1c between ≥7·7% and ≤11·0% [≥61·0 mmol/mol and ≤97·0 mmol/mol]) and had been prescribed insulin for at least 12 months before enrolment. After an 8 week lead-in period to optimise diabetes management, patients were randomly assigned (1:1:1) using an interactive voice response system to dapagliflozin 5 mg or 10 mg once daily, given orally, or matched placebo. Randomisation was stratified by current use of continuous glucose monitoring, method of insulin administration, and baseline HbA1c. The primary efficacy outcome was the change from baseline in HbA1c after 24 weeks of treatment in the full analysis set, which consisted of all randomly assigned patients who received at least one dose of study drug. An additional 55 patients who were incorrectly and non-randomly allocated to only dapagliflozin treatment groups were included in the safety analysis set. This study was registered with ClinicalTrials.gov, number NCT02268214; data collection for the present analysis was completed on Jan 4, 2017, and a 28 week extension phase is ongoing. Findings Between Nov 11, 2014, and April 16, 2016, 833 patients were assigned to treatment groups and included in safety analyses (dapagliflozin 5 mg [n=277] vs dapagliflozin 10 mg [n=296] vs placebo [n=260]; 778 of these patients were randomly assigned and included in the full analysis set for efficacy analyses (259 vs 259 vs 260; difference due to randomisation error affecting 55 patients). Mean baseline HbA1c was 8·53% (70 mmol/mol; SD 0·67% [7·3 mmol/mol]). At week 24, both doses of dapagliflozin significantly reduced HbA1c compared with placebo (mean difference from baseline to week 24 for dapagliflozin 5 mg vs placebo was −0·42% [95% CI −0·56 to −0·28; p

Summary Background The benefit of initiation of insulin pump therapy (continuous subcutaneous insulin infusion; CSII) in patients with type 1 diabetes using continuous glucose monitoring (CGM) has not been studied. We aimed to assess glycaemic outcomes when switching from multiple daily injections (MDI) to CSII in adults with type 1 diabetes using CGM. Methods In this multicentre, randomised controlled trial, 75 adults with type 1 diabetes in the CGM group of the DIAMOND trial were randomly assigned via the study website using a computer-generated sequence to continue MDI or switch to CSII, with continuation of CGM, for 28 weeks. The primary outcome was CGM-measured time in the glucose concentration range of 70–180 mg/dL (3·9–10·0 mmol/L). This study is registered with ClinicalTrials.gov, number NCT02282397. Findings Between April 14, 2015, and May 5, 2016, 37 participants were randomly assigned to the CGM plus CSII group and 38 participants were randomly assigned to the CGM plus MDI group. The study was completed by 36 (97%) of 37 participants in the CGM plus CSII group and 35 (92%) of 38 participants in the CGM plus MDI group. Mean CGM use was 6·7 days per week (SD 0·8) in the CGM plus CSII group and 6·9 days per week (0·3) in the CGM plus MDI group (p=0·86). No participants in the CGM plus CSII group who completed the trial discontinued CSII. Over the follow-up period, mean time in the glucose concentration range of 70–180 mg/dL (3·9–10·0 mmol/L) was 791 min per day (SD 157) in the CGM plus CSII group and 741 min per day (225) in the CGM plus MDI group (adjusted mean treatment group difference: 83 min, 95% CI 17–149; p=0·01). Participants in the CGM plus CSII group had a greater reduction in CGM-measured mean glucose (p=0·005) and hyperglycaemia (on four metrics: p=0·007 for >180 mg/dL [>10·0 mmol/L], p=0·02 for >250 mg/dL [>13·9 mmol/L], p=0·04 for >300 mg/dL [>16·6 mmol/L], and p=0·02 for the area under the curve for 180 mg/dL [10·0 mmol/L]), but also an increase in CGM-measured hypoglycaemia (p=0·0001 for 1c change from baseline to 28 weeks was 0·3% (SD 0·9; 3·3 mmol/mol [SD 9·8]) in the CGM plus CSII group and 0·1% (0·4; 1·1 mmol/mol [4·4]) in the CGM plus MDI group (p=0·32). Severe hypoglycaemia occurred in one participant in the CGM plus MDI group, and diabetic ketoacidosis and severe hyperglycaemia occurred in one participant each in the CGM plus CSII group. Interpretation Our findings show that glycaemic control measured by time in the glucose range of 70–180 mg/dL (3·9–10·0 mmol/L) is improved by initiation of CSII in adults with type 1 diabetes. However, biochemical hypoglycaemia also was increased in the study, which will be important to consider when incorporating these results into clinical practice. Funding Dexcom.

microRNAs are small regulatory RNAs that are currently emerging as new biomarkers for cancer and other diseases. In order for biomarkers to be useful in clinical settings, they should be accurately and reliably detected in clinical samples such as formalin fixed paraffin embedded (FFPE) sections and blood serum or plasma. These types of samples represent a challenge in terms of microRNA quantification. A newly developed method for microRNA qPCR using Locked Nucleic Acid (LNA)-enhanced primers enables accurate and reproducible quantification of microRNAs in scarce clinical samples. Here we show that LNA-based microRNA qPCR enables biomarker screening using very low amounts of total RNA from FFPE samples and the results are compared to microarray analysis data. We also present evidence that the addition of a small carrier RNA prior to total RNA extraction, improves microRNA quantification in blood plasma and laser capture microdissected (LCM) sections of FFPE samples.

Little is known about the life of William B. Boulton, who was active as an author in the 1900s. This illustrated two-volume set, published first in 1901 is perhaps the most famous of his works, though he also wrote biographies of Sir Joshua Reynolds and Thomas Gainsborough. The work examines how popular entertainment in London changed dramatically between the restoration of Charles II and the accession of Queen Victoria. From cock-fights and bear-baiting, tastes turned to less bloodthirsty pursuits, and led to the rise of many leisure activities that are still popular today. Volume 2 looks at the growth in popularity of outdoor pursuits in parks and gardens, fairs, the growth of clubs and coffee-houses, and the refinement of boxing from a crude, bare-knuckle contest into something resembling its modern form.

Cyclic AMP regulates the expression of a number of genes through a conserved promoter element, the CRE1. Moreover, transcrip-tional induction by cAMP requires the activation of cAMP-dependent protein kinase (protein kinase A)1,2. We have previously characterized the cAMP response element binding protein (CREB) in PC 12 cells and brain tissue as a nuclear factor, of relative molecular mass 43,000, whose transcriptional efficacy is regulated by protein kinase A phosphorylation3,4. CREB stimulates transcription on binding to the CRE as a dimer. Experiments suggesting that the dimerization and transcriptional efficacy of CREB are each stimulated by phosphorylation at distinct sites prompted us to suggest that CREB is regulated by multiple kinases in vivo4. We now report the isolation of a cDNA clone for rat CREB using amino-acid sequence information from purified CREB protein. Sequence analysis of this CREB cDNA predicts a cluster of protein kinase A, protein kinase C and casein kinase II consensus recognition sites near the N terminus of the protein. The proximity of these potential phosphorylation sites to one another indicates that they may interact either positively or negatively to regulate CREB bioactivity.