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AbstractObjective:FlexTouch* (FT) is a new prefilled insulin pen with no push-button extension at any set dose and a low activation force that is designed to improve ease of use and insulin administration. This paper reports the results of two usability studies assessing perceptions of FT compared with KwikPen† (KP)and SoloStar‡ (SS) among healthcare professionals (HCPs; both physicians and nurses) and people with diabetes (both insulin pen-experienced and insulin pen-naïve). *FlexTouch is a registered trade name of Novo Nordisk A/S, Bagsvaerd, Denmark.†KwikPen is a registered trade name of Eli Lilly & Co., Indianapolis, IN, USA.‡SoloStar is a registered trade name of Sanofi, Paris, France.Research design and methods:Participants were randomly assigned to start with FT or KP in one study and FT or SS in the other. Participants performed injections at different doses (20, 40 and 60 International Units [IU] in the FT vs. KP study or 20, 40 and 80 IU in the FT vs. SS study) into a foam cushion before answering questions on ease of use, teaching and learning, confidence and preference.Results:A total of 59 people with diabetes and 61 HCPs took part in the FT vs. SS study, and 79 people with diabetes and 81 HCPs took part in the FT vs. KP study. Considerably more patients and HCPs rated FT as very/fairly easy to inject with than KP or SS, particularly at the maximum dose (≥80% vs. ≤38% and ≤23%, respectively), and more were very/rather confident in the ability to manage daily insulin injections with FT than KP or SS. Overall, FT was rated significantly higher for ease of teaching and learning to use than KP or SS (all p < 0.001 vs. FT), and was preferred for teaching and learning compared with KP or SS (≥39% vs. ≤4% and ≤6%, respectively). More patients and HCPs would recommend FT (≥95%) than KP (≤72%) or SS (≤71%). The same pattern was generally seen across physicians, nurses, insulin pen-experienced and pen-naïve participants.Conclusions:The findings suggest that devices such as FT are easy to use and can be prescribed with relatively few training needs, which may improve ease of insulin initiation, increase pen use, and ultimately improve treatment adherence. A limitation of the usability questionnaire used in this study is that it did not assess the factors that influence preference. Further analyses could be conducted to determine the factors that appeal to different users. [ABSTRACT FROM AUTHOR]

ABSTRACTObjective:To compare safety and efficacy of biphasic insulin aspart 70/30 (BIAsp 30) with exenatide in subjects with type 2 diabetes mellitus (T2DM) not achieving glycemic targets with metformin and sulfonylurea in a randomized, open-label, 24-week trial.Research design and methods:Subjects (N  372, T2DM > 6 months, age ≥ 18 and ≤ 80 years, HbA1c ≥ 8, insulin naive not achieving glycaemic targets, receiving metformin and sulfonylurea) were randomized 1: 1: 1 to receive either BIAsp 30 QD (12 U before supper); BIAsp 30 BID (12 U divided equally between pre-breakfast and pre-supper); or exenatide (5 µg BID for 4 weeks and 10 µg BID thereafter). Efficacy (HbA1c, fasting plasma glucose [FPG]) and safety (adverse events and hypoglycemic episodes) were assessed.Results:Glycemic control achieved with both BIAsp 30 BID and BIAsp 30 QD was superior to that with exenatide (BIAsp 30 BID-exenatide: HbA1c difference −0.91 [95 CI: −1.23 to −0.59] and BIAsp 30 QD-exenatide: difference: −0.67 [95 CI: −0.99 to −0.34]). At the end of the study, more subjects achieved HbA1c < 7 and ≤ 6.5 in the BIAsp 30 BID group than in the exenatide group (HbA1c < 7: 37 vs. 20, p  0.0060; HbA1c ≤ 6.5: 25 vs. 8, p  0.0004, respectively). Combined hypoglycemic episodes (major, minor, symptoms only) were reported by 56, 61, and 29 of the subjects in the BIAsp 30 QD, BIAsp 30 BID, and exenatide groups, respectively. Weight gain was observed in the BIAsp 30 group (BIAsp 30 QD: 2.85 kg, BIAsp 30 BID: 4.08 kg) and weight loss was observed in the exenatide group (−1.96 kg). Nausea or vomiting was responsible for discontinuation of seven subjects in the exenatide group and one subject in the BIAsp 30 BID group.Conclusions:Significantly more T2DM patients (poorly controlled with combination metformin/sulfonylurea) achieved glycemic goals when treated with BIAsp 30 than with exenatide. The high baseline HbA1cvalues (∼10.2) and the long duration of diabetes (∼9 years) suggests that some subjects may have been in an advanced stage of their diabetes and may not have had sufficient β-cell function for a GLP-1 mimetic to be effective. The insulin-treated groups had more minor hypoglycemic events and weight gain but less gastrointestinal side-effects. In summary, BIAsp 30 was more efficacious in helping patients with high baseline HbA1cachieve glycemic goals.Clinical trial registration: www.clinicaltrials.gov, NCT00097877 [ABSTRACT FROM AUTHOR]

Continuous glucose monitoring (CGM) is an emerging tool for dietary counseling in athletes. This study aimed to explore blood glucose profiles in Para cyclists and evaluate CGM accuracy at rest and during exercise. Thirteen Para cyclists, comprising eight hand bikers and five cyclists, wore a CGM sensor (Abbott) for 2 weeks. Participants recorded the timing of meals and regular training sessions and executed one standardized training session. Fifteen capillary blood glucose reference values (seven at rest and eight during the standardized training) were obtained by finger pricks. Mean glucose concentrations and time spent in hypoglycemia (<3.9 mmol/L), euglycemia (3.9–7.8 mmol/L), and hyperglycemia (>7.8 mmol/L) were calculated over 24 hrs and during daytime, nighttime, exercise, and 2 hrs postprandial periods. Mean absolute relative differences (MARD) were calculated between the CGM and capillary blood glucose. The mean glucose concentration over the 24 hr‐period was 5.7 (5.6–5.8) mmol/L. Athletes were in the euglycemia range 91% of the time. Hyperglycemia was almost exclusively observed postprandially and during exercise. Hypoglycemia was restricted to the night and was particularly observed in athletes with a spinal cord injury. CGM accuracy was acceptable at rest (MARD: 12%) but markedly lower during exercise (MARD: 34%; p = 0.01), especially for hand bikers (MARD: 41%) compared with cyclists (MARD: 24%; p = 0.01). Para cyclists generally do not display signs of disturbed glucose regulation. However, the increased risk for nocturnal hypoglycemia in athletes with a spinal cord injury warrants attention. Furthermore, CGM accuracy is compromised during exercise, especially if the sensor is in proximity to highly active muscles. Highlights: Para cyclists generally do not display signs of disturbed glucose regulation.Para cyclists with a spinal cord injury seem to be at a higher risk for nocturnal hypoglycemia.Accuracy of the continuous glucose monitor is acceptable at rest but low during exercise, especially if the sensor is placed in proximity to highly active muscles. [ABSTRACT FROM AUTHOR]

The repeated evolution of phenotypes provides clear evidence for the role of natural selection in driving evolutionary change. However, the evolutionary origin of repeated phenotypes can be difficult to disentangle as it can arise from a combination of factors such as gene flow, shared ancestral polymorphisms or mutation. Here, we investigate the presence of these evolutionary processes in the Hawaiian spiny‐leg Tetragnatha adaptive radiation, which includes four microhabitat‐specialists or ecomorphs, with different body pigmentation and size (Green, Large Brown, Maroon, and Small Brown). We investigated the evolutionary history of this radiation using 76 newly generated low‐coverage, whole‐genome resequenced samples, along with phylogenetic and population genomic tools. Considering the Green ecomorph as the ancestral state, our results suggest that the Green ecomorph likely re‐evolved once, the Large Brown and Maroon ecomorphs evolved twice and the Small Brown evolved three times. We found that the evolution of the Maroon and Small Brown ecomorphs likely involved ancestral hybridization events, while the Green and Large Brown ecomorphs likely evolved through novel mutations, despite a high rate of incomplete lineage sorting in the dataset. Our findings demonstrate that the repeated evolution of ecomorphs in the Hawaiian spiny‐leg Tetragnatha is influenced by multiple evolutionary processes. [ABSTRACT FROM AUTHOR]

Aim: To use continuous glucose monitoring (CGM)‐based time‐in‐range (TIR) as a primary efficacy endpoint to compare the second‐generation basal insulin (BI) analogues insulin glargine 300 U/ml (Gla‐300) and insulin degludec 100 U/ml (IDeg‐100) in adults with type 1 diabetes (T1D). Materials and Methods: InRange was a 12‐week, multicentre, randomized, active‐controlled, parallel‐group, open‐label study comparing glucose TIR and variability between Gla‐300 and IDeg‐100 using blinded 20‐day CGM profiles. The inclusion criteria consisted of adults with T1D treated with multiple daily injections, using BI once daily and rapid‐acting insulin analogues for at least 1 year, with an HbA1c of 7% or higher and of 10% or less at screening. Results: Overall, 343 participants were randomized: 172 received Gla‐300 and 171 IDeg‐100. Non‐inferiority (10% relative margin) of Gla‐300 versus IDeg‐100 was shown for the primary endpoint (percentage TIR ≥ 70 to ≤ 180 mg/dl): least squares (LS) mean (95% confidence interval) 52.74% (51.06%, 54.42%) for Gla‐300 and 55.09% (53.34%, 56.84%) for IDeg‐100; LS mean difference (non‐inferiority): 3.16% (0.88%, 5.44%) (non‐inferiority P =.0067). Non‐inferiority was shown on glucose total coefficient of variation (main secondary endpoint): LS mean 39.91% (39.20%, 40.61%) and 41.22% (40.49%, 41.95%), respectively; LS mean difference (non‐inferiority) −5.44% (−6.50%, −4.38%) (non‐inferiority P <.0001). Superiority of Gla‐300 over IDeg‐100 was not shown on TIR. Occurrences of self‐measured and CGM‐derived hypoglycaemia were comparable between treatment groups. Safety profiles were consistent with known profiles, with no unexpected findings. Conclusions: Using clinically relevant CGM metrics, InRange shows that Gla‐300 is non‐inferior to IDeg‐100 in people with T1D, with comparable hypoglycaemia and safety profiles. [ABSTRACT FROM AUTHOR]

The bone morphogenic protein (BMP) family is a member of the TGF-beta superfamily and plays a crucial role during the onset of gut inflammation and arthritis diseases. Recent studies have reported a connection with the gut–joint axis; however, the genetic players are still less explored. Meanwhile, BDMC33 is a newly synthesized anti-inflammatory drug candidate. Therefore, in our present study, we analysed the genome-wide features of the BMP family as well as the role of BMP members in gut-associated arthritis in an inflammatory state and the ability of BDMC33 to attenuate this inflammation. Firstly, genome-wide analyses were performed on the BMP family in the zebrafish genome, employing several in silico techniques. Afterwards, the effects of curcumin analogues on BMP gene expression in zebrafish larvae induced with TNBS (0.78 mg/mL) were determined using real time-qPCR. A total of 38 identified BMP proteins were revealed to be clustered in five major clades and contain TGF beta and TGF beta pro peptide domains. Furthermore, BDMC33 suppressed the expression of four selected BMP genes in the TNBS-induced larvae, where the highest gene suppression was in the BMP2a gene (an eight-fold decrement), followed by BMP7b (four-fold decrement), BMP4 (four-fold decrement), and BMP6 (three-fold decrement). Therefore, this study reveals the role of BMPs in gut-associated arthritis and proves the ability of BDMC33 to act as a potential anti-inflammatory drug for suppressing TNBS-induced BMP genes in zebrafish larvae. [ABSTRACT FROM AUTHOR]

Background: Hormones play an indispensable role during fruit ripening, nine clades in 2-oxoglutarate-dependent dioxygenase (2OGD) superfamily are responsible for the hormone biosynthesis and metabolism, but less information is known about them. Results: A total of 163 Vv2OGD superfamily members were identified from grape genome, which were mainly expanded by local (tandem and proximal) duplication. Phylogenetic analysis of 2OGD members in grape and Arabidopsis indicates 37 members in Vv2OGD superfamily are related to hormone biosynthesis and metabolism process (Vv2OGD-H), which could be divided into 9 clades, gibberellin (GA) 3-oxidase (GA3ox), GA 20-oxidase (GA20ox), carbon-19 GA 2-oxidase (C19-GA2ox), carbon-20 GA 2-oxidase (C20-GA2ox), 1-aminocyclopropane-1-carboxylic acid oxidase (ACO), dioxygenase for auxin oxidation (DAO), lateral branching oxidoreductas (LBO), downy mildew resistant 6 and DMR6-like oxygenase (DMR6/DLO) and jasmonate-induced oxygenase (JOX). Sixteen of these 37 Vv2OGD-Hs are expressed in grape berry, in which the expression patterns of VvGA2oxs, VvDAOs and VvJOXs shows a correlation with the change patterns of GAs, indole-3-acetic acid (IAA) and jasmonates (JAs), indicating the involvement of these genes in grape berry development by regulating corresponding hormones. Twelve Vv2OGD-Hs respond to methyl JA (MeJA) treatment, of which eight may lead to the inhibition of the ripening process by the crosstalk of JAs-salicylic acids (SAs), JAs-GAs and JAs-JAs, while seven Vv2OGD-Hs respond to ABA treatment may be responsible for the promotion of ripening process by the interplay of abscisic acid (ABA)-strigolactones (SLs), ABA-SAs, ABA-GAs, ABA-JAs. Especially, VvLBO1 reach an expression peak near véraison and up-regulate about four times after ABA treatment, which implies SLs and ABA-SLs crosstalk may be related to the onset of berry ripening in grape. Conclusions: This study provides valuable clues and new insights for the mechanism research of Vv2OGD-Hs in hormones regulation during the grape berry development. [ABSTRACT FROM AUTHOR]

Insulin glargine is a long-acting insulin analog, which plays an important role in the treatment of diabetes mellitus. Biosimilar products of insulin glargine can provide patients with additional safe, high-quality, and potentially cost-effective options for treating diabetes. This article presents a randomized, double-blind, single-dose, two-treatment, four-period, replicate crossover, euglycemic clamp study which was designed to evaluate the PK and PD similarity between the recombinant insulin glargine developed by Wanbang (test) and Lantus® (reference) in healthy volunteers. Subjects received subcutaneous administration of the insulin glargine formulation (0.4 U/kg) on two occasions for the test and reference drug, respectively, and a 20% dextrose solution was infused at variable rate to clamp the blood glucose concentrations at 0.3 mmol/L below the subjects' fasting glucose for 24 h. Taking advantage of the improved sensitivity of the bioanalytical method applied and the solution of the matrix stability problem, the parent insulin glargine was determined in the vast majority of plasma samples using a fully validated UHPLC-MS/MS method. The PK characteristics of the parent insulin glargine were revealed for the first time: after subcutaneous injection, concentrations of the parent insulin glargine increased to a relative high level within 3 h, and then, a relatively flat concentration-time profile lasting for at least 12 h post-dose was observed. For the first time, the pharmacokinetic parameters of the parent insulin glargine were used as endpoints for similarity evaluation, which complied with the regulatory guidance better and made the similarity conclusion more powerful. The ratios of geometric means of all PK and PD endpoints were close to 100.00%. For the PK endpoints (AUC0-24h, Cmax, AUC0-12h, and AUC12-24h of the parent insulin glargine and its metabolite M1), the 90% confidence intervals of geometric mean ratios of test to reference were entirely contained within 80.00%-125.00%. For the PD endpoints [AUCGIR(0-24h), GIRmax, AUCGIR(0-12h), and AUCGIR(12-24h)], the 95% confidence intervals of geometric mean ratios of test to reference were entirely contained within 80.00%-125.00%. Based on the above mentioned results, it can be concluded that the PK and PD characteristics of the biosimilar drug developed by Wanbang are similar to those of Lantus. [ABSTRACT FROM AUTHOR]

Background: Pegloticase, a PEGylated uricase for uncontrolled gout, rapidly lowers serum urate (SU). Not all patients complete a full-therapy course because anti-pegloticase antibodies can develop, causing efficacy loss and infusion reactions. The literature and clinical trial data indicate that methotrexate co-administration markedly improves pegloticase response rates from the established monotherapy response rate of 42%. Unfortunately, methotrexate use is restricted by kidney disease, which is often present in uncontrolled gout patients. Leflunomide is less restricted in patients with renal dysfunction. This study examined the treatment response rate of pegloticase co-administered with leflunomide. Methods: Patients co-treated with pegloticase (8 mg biweekly infusion) and oral leflunomide (20 mg/day) were included. Patient/treatment characteristics and safety parameters (adverse events [AEs], laboratory parameters) were examined. Pre-infusion prophylaxis was administered (day of infusion: IV solumedrol, night before and morning of infusion: oral fexofenadine or diphenhydramine). Patients were considered treatment responders if ≥ 12 pegloticase infusions were administered and pre-infusion SU < 6 mg/dl at infusion-12. Results: Ten patients (five male, 72.7 ± 12.5 years) were included. The most common comorbidities were chronic kidney disease (90%), hypertension (70%), diabetes mellitus (60%), obesity (60%), and congestive heart failure (50%). Baseline SU was 7.1 ± 2.4 mg/dl and nine patients (90%) had subcutaneous tophi noted. Seven patients (70%) met responder criteria, receiving 26.6 ± 14.0 infusions (range 13–55) with a pre-infusion-12 SU of 0.9 ± 1.5 mg/dl. The three non-responders received < 12 infusions because of unrelated AEs or loss of follow-up. Three patients (30%) experienced AEs. One had unrelated cardiac disease worsening and three gout flares, one had a pre-infusion solumedrol reaction (wooziness/loss of consciousness), and one had two mild, transient increases in liver enzymes. Conclusions: This study supports leflunomide as co-therapy to pegloticase in uncontrolled gout patients. Heterogeneity and high comorbidity burden in uncontrolled gout patients makes having a variety of immunomodulators options important. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are non-coding RNAs with a special circular structure produced formed by the reverse splicing mechanism, which play an important role in a variety of biological activities. Viruses can encode circRNA, and viral circRNAs have been found in multiple single-stranded and double-stranded viruses. However, the characteristics and functions of viral circRNAs remain unknown. Sequence alignment showed that viral circRNAs are less conserved than circRNAs in animal, indicating that the viral circRNAs may evolve rapidly. Through the analysis of the sequence characteristics of viral circRNAs and circRNAs in animal, it was found that viral circRNAs and animals circRNAs are similar in nucleic acid composition, but have obvious differences in secondary structure and autocorrelation characteristics. Based on these characteristics of viral circRNAs, machine learning algorithms were employed to construct a prediction model to identify viral circRNA. Additionally, analysis of the interaction between viral circRNA and miRNAs showed that viral circRNA is expected to interact with 518 human miRNAs, and preliminary analysis of the role of viral circRNA. And it has been also found that viral circRNAs may be involved in many KEGG pathways related to nervous system and cancer. We curated an online server, and the data and code are available: http://server.malab.cn/viral-CircRNA/. [ABSTRACT FROM AUTHOR]

Background: Dasiglucagon, a next‐generation, ready‐to‐use aqueous glucagon analog formulation, has been developed to treat severe hypoglycemia in individuals with diabetes. Objective: The aim of this trial was to evaluate the safety and efficacy of dasiglucagon in pediatric individuals with type 1 diabetes (T1DM). Participants were children and adolescents (6–17 years) with T1DM. Methods: In this randomized double‐blind trial, 42 participants were randomly allocated (2:1:1) to a single subcutaneous (SC) injection of dasiglucagon (0.6 mg), placebo, or reconstituted glucagon (GlucaGen; dosed per label) during insulin‐induced hypoglycemia. The primary endpoint was time to plasma glucose (PG) recovery (first PG increase ≥20 mg/dL after treatment initiation without rescue intravenous glucose). The primary comparison was dasiglucagon vs. placebo; glucagon acted as a reference. Results: The median time (95% confidence interval) to PG recovery following SC injection was 10 min (8–12) for dasiglucagon vs. 30 min (20 to –) for placebo (P <.001); the median time for glucagon was 10 min (8–12), which did not include the time taken to reconstitute the lyophilized powder. PG recovery was achieved in all participants in the dasiglucagon and glucagon groups within 20 min of dosing compared to 2 out of 11 patients (18%) with placebo. The most frequent adverse events were nausea and vomiting, as expected with glucagon treatment. Conclusions: Consistent with adult phase 3 trials, dasiglucagon rapidly and effectively restored PG levels following insulin‐induced hypoglycemia in children and adolescents with T1DM, with an overall safety profile similar to glucagon. [ABSTRACT FROM AUTHOR]

Evidence from randomized controlled trials (RCTs) has shown that second‐generation basal insulin (BI) analogues, insulin glargine 300 U/mL (Gla‐300) and insulin degludec (IDeg), provide similar glycaemic control, with a lower risk of hypoglycaemia compared with the first‐generation BI analogue insulin glargine 100 U/mL (Gla‐100) in people with type 2 diabetes (T2D). However, the highly selected participants and frequent follow‐up of RCTs may not be truly representative of real‐life clinical practice. It is important to assess the safety and effectiveness of these second‐generation BI analogues in real‐life clinical practice settings. The DELIVER programme utilized electronic healthcare records from the United States to compare clinical outcomes in people with T2D who received either Gla‐300 or other BI analogues in real‐world clinical practice. This review provides a concise overview of the results of the DELIVER studies. Overall, Gla‐300 provided similar antihyperglycaemic effectiveness and a lower risk of hypoglycaemia versus the first‐generation BI analogues Gla‐100 and insulin detemir in people with T2D who had switched BIs. In those who were insulin‐naïve, initiation with Gla‐300 versus Gla‐100 was associated with significantly better antihyperglycaemic effectiveness and similar or lower hypoglycaemic risk. Both glycaemic control and hypoglycaemia risk were also shown to be similar with Gla‐300 and IDeg, in people who had switched BIs and in those who were insulin‐naïve. In addition, the DELIVER 2 study reported that people with T2D who switched to Gla‐300 had reduced healthcare resource utilization, with an overall saving of US$1439 per person per year compared with those who switched to another BI analogue. Overall, the real‐world DELIVER programme showed that the glycaemic control with a low risk of hypoglycaemia observed with Gla‐300 in RCTs was also seen in standard clinical practice. [ABSTRACT FROM AUTHOR]

Introduction: Gout is a painful inflammatory condition caused by chronically elevated serum uric acid levels (sUA). When standard urate-lowering therapies fail/are not tolerated, uncontrolled gout (elevated sUA, subcutaneous tophi, chronic gouty arthritis, frequent flares) can occur. Pegloticase, a recombinant uricase, converts uric acid to allantoin, a readily excreted molecule. Responder rate in trials was 42%, limited by anti-drug antibody (ADA) development. Immunomodulators attenuate ADA formation and case reports suggest immunomodulation increases pegloticase responder rates. The current study retrospectively examined responder rate in patients undergoing methotrexate/pegloticase co-therapy. Methods: Patients who underwent methotrexate/pegloticase co-treatment at a single rheumatology practice were included. Demographics, clinical, treatment, and safety parameters were collected. The primary outcome was the proportion of responders (≥ 12 biweekly pegloticase infusions, sUA < 6 mg/dl just prior to infusion 12). Results: Ten patients (nine men, 52.3 ± 13.5 years) with uncontrolled tophaceous gout (erosive damage, ulcerative tophi, frequent flares, gout-related hospitalizations) were included. Patients had failed allopurinol (100–300 mg) or febuxostat (40 mg) therapy (doses not increased because of intolerance, kidney concerns, noncompliance, or rapid tophi resolution requirement). Baseline sUA was 9.42 ± 2.05 mg/dl. Along with standard pre-infusion prophylaxis, nine patients received subcutaneous methotrexate (25 mg/week) initiated 14–35 days before pegloticase and one patient received oral methotrexate (12.5 mg/week) initiated 14 days after pegloticase. Eight patients (80%) were responders, receiving 15.5 ± 3.8 infusions (range, 12–21) over 31.8 ± 9.5 weeks. One patient had efficacy loss with mild infusion reaction during infusion 4 and one patient was lost to follow-up after infusion 5. One patient reported one gout flare. No new safety concerns emerged. Conclusions: Methotrexate/pegloticase co-therapy resulted in a higher responder rate than the established 42% with pegloticase alone. Therefore, methotrexate/pegloticase co-therapy may safely allow more patients to benefit from a full treatment course, likely through ADA attenuation. Plain Language Summary: Uncontrolled gout is a painful inflammatory condition caused by excess uric acid in the blood. When standard oral medicines used to lower uric acid do not work or cannot be taken, pegloticase is the only remaining treatment option. Unfortunately, less than half of patients respond to pegloticase for an adequate amount of time because their immune system develops antibodies against the medicine, causing the medicine to be quickly removed from the body preventing a durable or prolonged response. Methotrexate has been shown to limit or prevent this immune response in patients treated with biologic therapies for autoimmune diseases. The current study found that eight of ten patients (80%) treated with both methotrexate and pegloticase responded to treatment (received 12 or more biweekly pegloticase doses and had low uric acid levels in their blood just before infusion 12). No new side effects or safety concerns were reported. In this retrospective study, methotrexate appeared to allow more patients to benefit from a full course of pegloticase therapy. [ABSTRACT FROM AUTHOR]

This study was conducted to explore specific chill models and the mechanisms underlying rhizome bud dormancy break in Polygonatum kingianum. Rhizome buds were subjected to various chilling temperatures for different duration and then transferred to warm conditions for germination and subsequent evaluation of their response to temperature and chilling requirements. A CUkingianum model was constructed to describe the contribution of low temperature to the chill unit, and it was suggested that 2.97°C was the optimum temperature and that 11.54°C was the upper limit for bud release. The CASkingianum model showed the relationship between chilling accumulation and sprouting percentage; therefore, rhizome bud development could be predicted through the model. Weighted correlation network analysis (WGCNA) of transcriptomic data of endo-, eco- and nondormant rhizome buds generated 33 gene modules, 6 of which were significantly related to bud sprouting percentage. In addition, 7 significantly matched transcription factors (TFs) were identified from the promoters of 17 "real" hub genes, and DAG2 was the best matched TF that bound to AAAG element to regulate gene expression. The current study is valuable for developing a highly efficient strategy for seedling cultivation and provides strong candidates for key genes related to rhizome bud dormancy in P. kingianum. [ABSTRACT FROM AUTHOR]

Introduction: The LIGHTNING study applied conventional and advanced analytic approaches to model, predict, and compare hypoglycemia rates of people with type 2 diabetes (T2DM) on insulin glargine 300 U/ml (Gla-300) with those on first-generation (insulin glargine 100 U/ml [Gla-100]; insulin detemir [IDet]) or second-generation (insulin degludec [IDeg]) basal-insulin (BI) analogs, utilizing a large real-world database. Methods: Data were collected between 1 January 2007 and 31 March 2017 from the Optum Humedica US electronic health records [EHR] database. Patient-treatments, the period during which a patient used a specific BI, were analyzed for patients who switched from a prior BI or those who newly initiated BI therapy. Data were analyzed using two approaches: propensity score matching (PSM) and a predictive modeling approach using machine learning. Results: A total of 831,456 patients with T2DM receiving BI were included from the EHR data set. Following selection, 198,198 patient-treatments were available for predictive modeling. The analysis showed that rates of severe hypoglycemia (using a modified definition) were approximately 50% lower with Gla-300 than with Gla-100 or IDet in insulin-naïve individuals, and 30% lower versus IDet in BI switchers (all p < 0.05). Similar rates of severe hypoglycemia were predicted for Gla-300 and IDeg, regardless of prior insulin experience. Similar results to those observed in the overall cohorts were seen in analyses across subgroups at a particularly high risk of hypoglycemia. PSM (performed on 157,573 patient-treatments) revealed comparable reductions in HbA1c with Gla-300 versus first- and second-generation BI analogs, alongside lower rates of severe hypoglycemia with Gla-300 versus first-generation BI analogs (p < 0.05) and similar rates versus IDeg in insulin-naïve and BI-switcher cohorts. Conclusions: Based on real-world data, predicted rates of severe hypoglycemia with Gla-300 tended to be lower versus first-generation BI analogs and similar versus IDeg in a wide spectrum of patients with T2DM. Funding: Sanofi, Paris, France. [ABSTRACT FROM AUTHOR]

Importance: Hypoglycemia, common in patients with type 1 diabetes, is a major barrier to achieving good glycemic control. Severe hypoglycemia can lead to coma or death.Objective: To determine whether insulin degludec is noninferior or superior to insulin glargine U100 in reducing the rate of symptomatic hypoglycemic episodes.Design, Setting, and Participants: Double-blind, randomized, crossover noninferiority trial involving 501 adults with at least 1 hypoglycemia risk factor treated at 84 US and 6 Polish centers (January 2014-January 12, 2016) for two 32-week treatment periods, each with a 16-week titration and a 16-week maintenance period.Interventions: Patients were randomized 1:1 to receive once-daily insulin degludec followed by insulin glargine U100 (n = 249) or to receive insulin glargine U100 followed by insulin degludec (n = 252) and randomized 1:1 to morning or evening dosing within each treatment sequence.Main Outcomes and Measures: The primary end point was the rate of overall severe or blood glucose-confirmed (<56 mg/dL) symptomatic hypoglycemic episodes during the maintenance period. Secondary end points included the rate of nocturnal symptomatic hypoglycemic episodes and proportion of patients with severe hypoglycemia during the maintenance period. The noninferiority criterion for the primary end point and for the secondary end point of nocturnal hypoglycemia was defined as an upper limit of the 2-sided 95% CI for a rate ratio of 1.10 or lower; if noninferiority was established, 2-sided statistical testing for superiority was conducted.Results: Of the 501 patients randomized (mean age, 45.9 years; 53.7% men), 395 (78.8%) completed the trial. During the maintenance period, the rates of overall symptomatic hypoglycemia were 2200.9 episodes per 100 person-years' exposure (PYE) in the insulin degludec group vs 2462.7 episodes per 100 PYE in the insulin glargine U100 group for a rate ratio (RR) of 0.89 (95% CI, 0.85-0.94; P < .001 for noninferiority; P < .001 for superiority; rate difference, -130.31 episodes per 100 PYE; 95% CI, -193.5 to -67.16). The rates of nocturnal symptomatic hypoglycemia were 277.1 per 100 PYE in the insulin degludec group vs 428.6 episodes per 100 PYE in the insulin glargine U100 group, for an RR of 0.64 (95% CI, 0.56-0.73; P < .001 for noninferiority; P < .001 for superiority; rate difference, -61.94 episodes per 100 PYE; 95% CI, -83.85 to -40.03). A lower proportion of patients in the insulin degludec than in the insulin glargine U100 group experienced severe hypoglycemia during the maintenance period (10.3%, 95% CI, 7.3%-13.3% vs 17.1%, 95% CI, 13.4%-20.8%, respectively; McNemar P = .002; risk difference, -6.8%; 95% CI, -10.8% to -2.7%).Conclusions and Relevance: Among patients with type 1 diabetes and at least 1 risk factor for hypoglycemia, 32 weeks' treatment with insulin degludec vs insulin glargine U100 resulted in a reduced rate of overall symptomatic hypoglycemic episodes.Trial Registration: clinicaltrials.gov Identifier: NCT02034513. [ABSTRACT FROM AUTHOR]

The article lists 2016 Reviewers from 1 January 2016 through 15 December 2016.

The article presents scientific abstracts on topics including drug interactions, ambulatory care and critical care.

Since the early 2000s, continuous glucose monitoring (CGM) technology has advanced to become a standard of care in the treatment of type 1 diabetes. Unfortunately, CGM use is not commonly integrated into practice. This article will review the history, technology, and need for systematic training in CGM. Additionally, it will review recent clinical trial data demonstrating the benefits that CGM offers to all people with type 1 diabetes and the clinicians who care for them. [ABSTRACT FROM AUTHOR]

Aims To compare 24-hour fixed-time basal insulin peglispro ( BIL) dosing with 8- to 40-hour variable-time BIL dosing for glycaemic control and safety in patients with type 1 diabetes. Primary outcome was non-inferiority of BIL variable-time dosing compared with fixed-time dosing for glycated haemoglobin ( HbA1c) change after 12-week treatment (margin = 0.4%). Materials and methods This Phase 3, open-label, randomized, cross-over study ( N = 212) was conducted at 20 centres in the United States. During the 12-week lead-in phase, patients received BIL daily at fixed-times. Two 12-week randomized cross-over treatment phases followed, where patients received BIL dosed at either fixed- or variable-times. During the 4-week safety follow-up, patients received conventional insulins. Results During the lead-in period, least-squares mean HbA1c decreased from 7.5% to 6.8%. For BIL, variable-time dosing was non-inferior to fixed-time dosing for HbA1c change [least-squares mean difference = 0.06%, 95% confidence interval (−0.01, 0.13)]. In both regimens, HbA1c increased slightly during the cross-over periods, but remained significantly below baseline. Variable- and fixed-time dosing regimens had similar rates of total hypoglycaemia (10.4 ± 0.62 and 10.5 ± 0.67 events/patient/30 days, P = .947) and nocturnal hypoglycaemia (1.3 ± 0.11 and 1.5 ± 0.13 events/patient/30days, P = .060). Comparable proportions of patients achieved HbA1c < 7.0% with variable- [91 (54.5%)] and fixed-time dosing [101 (60.5%)]. Conclusions Treatment with BIL allows patients to use flexible dosing intervals from 8 to 40 hours. Glycaemic efficacy ( HbA1c), glycaemic variability and hypoglycaemia are similar to fixed-time dosing, suggesting that BIL could potentially provide flexibility in dosing for patients who miss their daily basal insulin. [ABSTRACT FROM AUTHOR]

Rationale: There is uncertainty about the effects of treating obstructive sleep apnea on glycemic control in patients with type 2 diabetes.Objectives: To determine whether treatment of obstructive sleep apnea in patients with type 2 diabetes improves glycemic control.Methods: In this trial, we randomized patients with type 2 diabetes and no previous diagnosis of obstructive sleep apnea, with a glycated hemoglobin level of 6.5-8.5%, and an oxygen desaturation index of 15 or more events per hour to positive airway pressure therapy or to usual care.Measurements and Main Results: A total of 416 patients met the entry criteria as determined by each site and were randomized. Of the 298 participants who met centrally adjudicated entry criteria, no differences between the study groups were seen for change in glycated hemoglobin. Furthermore, there were no between-group differences when analyses were restricted to those with poorer baseline glycemic control, those with more severe sleep apnea, or those who were adherent to therapy. A greater fall in diastolic blood pressure occurred in the positive airway pressure group than in the usual care group (-3.5 mm Hg vs. -1.5 mm Hg; P = 0.07). This difference was significant in those who were adherent to positive airway pressure therapy (-4.4 mm Hg vs. -1.6 mm Hg; P = 0.02). There was a significant reduction in sleepiness in the positive airway pressure therapy group (P < 0.0001). Quality of life assessment revealed improvements in vitality, mental health, and mental component summary scores in the positive airway pressure therapy group.Conclusions: This trial showed no effect of positive airway pressure therapy on glycemic control in patients with relatively well-controlled type 2 diabetes and obstructive sleep apnea. Clinical trial registered with www.clinicaltrials.gov (NCT00509223). [ABSTRACT FROM AUTHOR]

Importance: Few cardiovascular outcomes trials have been conducted for obesity treatments. Withdrawal of 2 marketed drugs has resulted in controversy about the cardiovascular safety of obesity agents.Objective: To determine whether the combination of naltrexone and bupropion increases major adverse cardiovascular events (MACE, defined as cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction) compared with placebo in overweight and obese patients.Design, Setting, and Participants: Randomized, multicenter, placebo-controlled, double-blind noninferiority trial enrolling 8910 overweight or obese patients at increased cardiovascular risk from June 13, 2012, to January 21, 2013, at 266 US centers. After public release of confidential interim data by the sponsor, the academic leadership of the study recommended termination of the trial and the sponsor agreed.Interventions: An Internet-based weight management program was provided to all participants. Participants were randomized to receive placebo (n=4454) or naltrexone, 32 mg/d, and bupropion, 360 mg/d (n=4456).Main Outcomes and Measures: Time from randomization to first confirmed occurrence of a MACE. The primary analysis planned to assess a noninferiority hazard ratio (HR) of 1.4 after 378 expected events, with a confidential interim analysis after approximately 87 events (25% interim analysis) to assess a noninferiority HR of 2.0 for consideration of regulatory approval.Results: Among the 8910 participants randomized, mean age was 61.0 years (SD, 7.3 years), 54.5% were female, 32.1% had a history of cardiovascular disease, and 85.2% had diabetes, with a median body mass index of 36.6 (interquartile range, 33.1-40.9). For the 25% interim analysis, MACE occurred in 59 placebo-treated patients (1.3%) and 35 naltrexone-bupropion-treated patients (0.8%; HR, 0.59; 95% CI, 0.39-0.90). After 50% of planned events, MACE occurred in 102 patients (2.3%) in the placebo group and 90 patients (2.0%) in the naltrexone-bupropion group (HR, 0.88; adjusted 99.7% CI, 0.57-1.34). Adverse effects were more common in the naltrexone-bupropion group, including gastrointestinal events in 14.2% vs 1.9% (P < .001) and central nervous system symptoms in 5.1% vs 1.2% (P < .001).Conclusions and Relevance: Among overweight or obese patients at increased cardiovascular risk, based on the interim analyses performed after 25% and 50% of planned events, the upper limit of the 95% CI of the HR for MACE for naltrexone-bupropion treatment, compared with placebo, did not exceed 2.0. However, because of the unanticipated early termination of the trial, it is not possible to assess noninferiority for the prespecified upper limit of 1.4. Accordingly, the cardiovascular safety of this treatment remains uncertain and will require evaluation in a new adequately powered outcome trial.Trial Registration: clinicaltrials.gov Identifier: NCT01601704. [ABSTRACT FROM AUTHOR]