Combination SGLT2 Inhibitor and Glucagon Receptor Antagonist Therapy in Type 1 Diabetes: A Randomized Clinical Trial.

OBJECTIVE: To examine the effects of insulin-adjunctive therapy with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and a glucagon receptor antagonist (GRA) on glycemia, insulin use, and ketogenesis during insulinopenia in type 1 diabetes. RESEARCH DESIGN AND METHODS: In a randomized, double-blind, placebo-controlled, crossover trial we assessed the effects of adjunctive SGLT2 inhibitor therapy (dapagliflozin 10 mg daily) alone and in combination with the GRA volagidemab (70 mg weekly) in 12 adults with type 1 diabetes. Continuous glucose monitoring, insulin dosing, and insulin withdrawal tests (IWT) for measurement of glucose and ketogenesis during insulinopenia were completed during insulin-only (Baseline), SGLT2 inhibitor, and combination (SGLT2 inhibitor + GRA) therapy periods. RESULTS: Average glucose and percent time with glucose in range (70-180 mg/dL) improved with combination therapy versus Baseline and SGLT2 inhibitor (131 vs. 150 and 138 mg/dL [P < 0.001 and P = 0.01] and 86% vs. 70% and 78% [P < 0.001 and P = 0.03], respectively) without increased hypoglycemia. Total daily insulin use decreased with combination therapy versus Baseline and SGLT2 inhibitor (0.41 vs. 0.56 and 0.52 units/kg/day [P < 0.001 and P = 0.002]). Peak ß-hydroxybutyrate levels during IWT were lower with combination therapy than with SGLT2 inhibitor (2.0 vs. 2.4 mmol/L; P = 0.048) and similar to levels reached during the Baseline testing period (2.1 mmol/L). Participants reported enhanced treatment acceptability and satisfaction with combination therapy. CONCLUSIONS: Glucagon antagonism enhances the therapeutic effects of SGLT2 inhibition in type 1 diabetes. Combination therapy improves glycemic control, reduces insulin dosing, and suggests a strategy to unlock the benefits of SGLT2 inhibitors while mitigating the risk of diabetic ketoacidosis.

Astaxanthin, a natural antioxidant, lowers cholesterol and markers of cardiovascular risk in individuals with prediabetes and dyslipidaemia.

AIM: To determine the effects of astaxanthin treatment on lipids, cardiovascular disease (CVD) markers, glucose tolerance, insulin action and inflammation in individuals with prediabetes and dyslipidaemia. MATERIALS AND METHODS: Adult participants with dyslipidaemia and prediabetes (n = 34) underwent baseline blood draw, an oral glucose tolerance test and a one-step hyperinsulinaemic-euglycaemic clamp. They were then randomized (n = 22 treated, 12 placebo) to receive astaxanthin 12 mg daily or placebo for 24 weeks. Baseline studies were repeated after 12 and 24 weeks of therapy. RESULTS: After 24 weeks, astaxanthin treatment significantly decreased low-density lipoprotein (-0.33 ± 0.11 mM) and total cholesterol (-0.30 ± 0.14 mM) (both P < .05). Astaxanthin also reduced levels of the CVD risk markers fibrinogen (-473 ± 210 ng/mL), L-selectin (-0.08 ± 0.03 ng/mL) and fetuin-A (-10.3 ± 3.6 ng/mL) (all P < .05). While the effects of astaxanthin treatment did not reach statistical significance, there were trends toward improvements in the primary outcome measure, insulin-stimulated, whole-body glucose disposal (+0.52 ± 0.37 mg/m2 /min, P = .078), as well as fasting [insulin] (-5.6 ± 8.4 pM, P = .097) and HOMA2-IR (-0.31 ± 0.16, P = .060), suggesting improved insulin action. No consistent significant differences from baseline were observed for any of these outcomes in the placebo group. Astaxanthin was safe and well tolerated with no clinically significant adverse events. CONCLUSIONS: Although the primary endpoint did not meet the prespecified significance level, these data suggest that astaxanthin is a safe over-the-counter supplement that improves lipid profiles and markers of CVD risk in individuals with prediabetes and dyslipidaemia.

The impact of a structured one-day seminar on disease-specific knowledge, lifestyle habits and disease impairment in ANCA-associated vasculitis. Results of a randomized, controlled study.

OBJECTIVE: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a complex, chronic autoimmune disease, and its diagnosis triggers considerable anxiety and uncertainty for those affected. There are currently no valid data describing the impact of disease-specific patient education on the disease knowledge, subjective impairment, and changes in lifestyle habits related to AAV. METHOD: We designed a one-day educational programme to serve AAV patients with information about their disease and its treatment. Patients were randomized into an intervention group and a waiting list control group. Increase in knowledge was measured with a multiple-choice test. The intervention group completed the questionnaire before, directly after, and 3 months after the seminar, while the waiting list control group was additionally tested 3 months before the seminar to rule out non-specific learning. Furthermore, we investigated the burden of the disease and the impact of our intervention on this burden. RESULTS: Compared with the control group, the intervention increased the knowledge (mean ± sd score difference 2.2 ± 1.0, 95% confidence interval 0.1-4.3, p = 0.04). From the patients' point of view, their understanding of the disease had improved and the subjective impairment caused by their rheumatic disease had decreased. There was a tendency to include disease-relevant behaviour, such as nasal care or dietary recommendations, more often in everyday life. CONCLUSION: A one-day seminar is suitable to increase the disease-specific knowledge of patients with AAV in a sustainable manner. In addition, our measure positively affected the disease-relevant behaviour.

Glucagon receptor antagonist volagidemab in type 1 diabetes: a 12-week, randomized, double-blind, phase 2 trial.

Hyperglucagonemia contributes to hyperglycemia in patients with type 1 diabetes (T1D); however, novel therapeutics that block glucagon action could improve glycemic control. This phase 2 study evaluated the safety and efficacy of volagidemab, an antagonistic monoclonal glucagon receptor (GCGR) antibody, as an adjunct to insulin therapy in adults with T1D. The primary endpoint was change in daily insulin use at week 12. Secondary endpoints included changes in hemoglobin A1c (HbA1c) at week 13, in average daily blood glucose concentration and time within target range as assessed by continuous blood glucose monitoring (CGM) and seven-point glucose profile at week 12, incidence of hypoglycemic events, the proportion of subjects who achieve HbA1c reduction of ≥0.4%, volagidemab drug concentrations and incidence of anti-drug antibodies. Eligible participants (n = 79) were randomized to receive weekly subcutaneous injections of placebo, 35 mg volagidemab or 70 mg volagidemab. Volagidemab produced a reduction in total daily insulin use at week 12 (35 mg volagidemab: -7.59 units (U) (95% confidence interval (CI) -11.79, -3.39; P = 0.040 versus placebo); 70 mg volagidemab: -6.64 U (95% CI -10.99, -2.29; P = 0.084 versus placebo); placebo: -1.27 U (95% CI -5.4, 2.9)) without meeting the prespecified significance level (P < 0.025). At week 13, the placebo-corrected reduction in HbA1c percentage was -0.53 (95% CI -0.89 to -0.17, nominal P = 0.004) in the 35 mg volagidemab group and -0.49 (95% CI -0.85 to -0.12, nominal P = 0.010) in the 70 mg volagidemab group. No increase in hypoglycemia was observed with volagidemab therapy; however, increases in serum transaminases, low-density lipoprotein (LDL)-cholesterol and blood pressure were observed. Although the primary endpoint did not meet the prespecified significance level, we believe that the observed reduction in HbA1c and tolerable safety profile provide a rationale for further randomized studies to define the long-term efficacy and safety of volagidemab in patients with T1D.

Impact of the hepatoselective glucokinase activator TTP399 on ketoacidosis during insulin withdrawal in people with type 1 diabetes.

AIMS: To determine the effect of TTP399, a hepatoselective glucokinase activator, on the risk of ketoacidosis during insulin withdrawal in individuals with type 1 diabetes (T1D). MATERIALS AND METHODS: Twenty-three participants with T1D using insulin pump therapy were randomized to 800 mg TTP399 (n = 12) or placebo (n = 11) for 7 to 10 days. After the treatment period, an insulin withdrawal test (IWT) was performed, during which insulin pumps were removed to induce ketogenesis. The IWT was stopped after 10 hours or if blood glucose reached >399 mg/dL [22.1 mmol/L], if beta-hydroxybutyrate (BHB) was >3.0 mmol/L, or for patient discomfort. The primary endpoint was the proportion of participants who reached BHB concentrations of 1 mmol/L or greater. RESULTS: During the 7- to 10-day treatment period, mean fasting plasma glucose was significantly reduced ( -27.6 vs. -4.4 mg/dL [-1.5 vs. -0.2 mmol/L]; P = 0.03) and there were fewer adverse events, including hypoglycaemia, in the TTP399-treated arm. During the IWT, no differences were observed between TTP399 and placebo in mean serum BHB concentration, mean duration of IWT, or BHB at termination of IWT. However, serum bicarbonate was numerically higher and urine acetoacetate was quantitatively lower in the TTP399-treated participants. As a result of higher bicarbonate values, none of the TTP399-treated participants met the prespecified criteria for diabetic ketoacidosis (DKA), defined as BHB >3 mmol/L and serum bicarbonate <18 mEq/L, compared to 42% of placebo-treated participants. CONCLUSIONS: When used as an adjunctive therapy to insulin, TTP399 improves glycaemia without increasing hypoglycaemia in individuals with T1D. During acute insulin withdrawal, TTP399 did not increase BHB concentrations and decreased the incidence of DKA.

SGLT2 Inhibition Increases Fasting Glucagon but Does Not Restore the Counterregulatory Hormone Response to Hypoglycemia in Participants With Type 1 Diabetes.

Individuals with type 1 diabetes have an impaired glucagon counterregulatory response to hypoglycemia. Sodium-glucose cotransporter (SGLT) inhibitors increase glucagon concentrations. We evaluated whether SGLT inhibition restores the glucagon counterregulatory hormone response to hypoglycemia. Adults with type 1 diabetes (n = 22) were treated with the SGLT2 inhibitor dapagliflozin (5 mg daily) or placebo for 4 weeks in a randomized, double-blind, crossover study. After each treatment phase, participants underwent a hyperinsulinemic-hypoglycemic clamp. Basal glucagon concentrations were 32% higher following dapagliflozin versus placebo, with a median within-participant difference of 2.75 pg/mL (95% CI 1.38-12.6). However, increased basal glucagon levels did not correlate with decreased rates of hypoglycemia and thus do not appear to be protective in avoiding hypoglycemia. During hypoglycemic clamp, SGLT2 inhibition did not change counterregulatory hormone concentrations, time to recovery from hypoglycemia, hypoglycemia symptoms, or cognitive function. Thus, despite raising basal glucagon concentrations, SGLT inhibitor treatment did not restore the impaired glucagon response to hypoglycemia. We propose that clinical reduction in hypoglycemia associated with these agents is a result of changes in diabetes care (e.g., lower insulin doses or improved glycemic variability) as opposed to a direct, physiologic effect of these medications on α-cell function.

[Neurofibroma in Children hand - Case Report and Literature Review]. / Neurofibrome an der kindlichen Hand ­ Fallbericht und Literaturrecherche.

Neurofibromas rarely occur before the age of 7 in children. They are a rarity on the hand, especially if they are accompanied by sensory disturbances and impairment of the gripping function. We report on a 9-year-old girl with symptomatic neurofibroma of the third and fourth ray of the right palm.

[Slowly progressive joint destruction in an older man as expression of hydroxyapatite disease. Case report and literature review]. / Langsam progrediente Gelenkzerstörung bei einem älteren Mann als Ausdruck einer Hydroxylapatiterkrankung. Fallbericht und Literaturübersicht.

This article reports the case of a 75-year-old male patient presenting with arthralgia of the large joints that had existed for 10 years. Clinically, bursitis of the right elbow joint was found. Laboratory tests showed elevated inflammatory markers and imaging revealed erosive joint destruction. A surgical bursectomy was performed. Histologically, hydroxyapatite crystals were detected in alizarin red S staining and a crystal arthropathy was diagnosed. The diagnostics are difficult since crystals can only be detected by electron microscopy or special staining methods.

[Attending physicians in urology working at university centers or non-university centers-what are the differences? : Results of a web-based cross-sectional study at German hospitals]. / Urologische Oberärztinnen und Oberärzte an universitären oder nicht-universitären Kliniken ­ welche Unterschiede gibt es? : Ergebnisse einer webbasierten Querschnittstudie an deutschen Kliniken.

BACKGROUND: Attending physicians (AP) in urology represent a very heterogeneous group covering various clinical priorities and career objectives. To date, there are no reliable data on professional, personal and position-linked aspects of AP in urology working in university centers (univ-AP) opposed to those working in non-university centers (n-univ-AP). MATERIALS AND METHODS: The objective of this study was to analyze individual professional perspectives, professional and personal settings, specific job-related activities and individual professional goals of univ-AP opposed to n­univ-AP. Thus, a web-based survey containing 55 items was designed to perform a cross-sectional study that was then forwarded using a link which was sent via a mailing list of the German Society of Urology. The survey was available for completion by AP at German urological centers from February to April 2019. Group-specific differences were evaluated using bootstrap-adjusted multivariate logistic regression models. RESULTS: Of the 192 evaluable surveys, 61 (31.8%) and 131 (68.2%) were part of the univ-AP and n­univ-AP study group, respectively. Participating n­univ-AP compared to univ-AP held the position of AP (p = 0.022) significantly longer and were on call significantly more frequently (p < 0.001). AP in urology (self)-assessed themselves as autonomously confident in performing robotic, laparoscopic, open, endo-urologic, and plastic-reconstructive surgery in 12.4%, 25%, 59.6%, 92.1%, and 25.7%, respectively, with no significant differences between the two groups among all above mentioned surgical subdomains based on multivariate analysis. AP in urology were (very) content in 92% concerning the choice of their discipline, in 73.9% concerning their actual working circumstances, and in 60.2% concerning their level of surgical expertise. Only 27.1% and 19.9% were (very) content with the amount of available time for their personal professional development and for private affairs, respectively. As opposed to n­univ-AP, univ-AP would choose a career in clinical centers once again significantly more frequently (OR 2.87; p(BS) = 0.041), but assess the position of AP as their definitive career goal significantly less frequently (OR 0.42; p(BS) = 0.40). Univ-AP state significantly more frequently that they were running for the position of head of department or full professor (OR 5.64; p(BS) = 0.001). CONCLUSION: In this first survey study world-wide on AP in urology divided according to their academic background, similarities and variances were analyzed, baring the potential to further improve identification of AP for a career in clinical centers.

Endoscopic full-thickness resection (EFTR) in the lower gastrointestinal tract.

BACKGROUND: Endoscopic full-thickness resection (EFTR) significantly expands the spectrum of endoscopic colorectal resection methods for lesions that show no lifting sign, submucosal lesions and mucosal carcinomas. The aim of our study was to evaluate the efficacy and safety of EFTR using a commercially available full thickness resection device (FTRD) by assessing the completeness of the full-thickness resection, the technical success, as well as complications in a cohort of patients from three referral centers in Germany. Another aim was to determine which patient subpopulations benefit most in clinical practice. METHODS: This retrospective multicenter study was conducted on consecutive patients who were admitted to three referral centers in Germany between November 2014 and December 2017. The EFTR was conducted according to the standard indications using the FTRD System (OVESCO, Tübingen, Germany). Data were obtained from prospectively maintained institutional databases. RESULTS: There were 70 patients, 42 males and 25 females with a mean age of 79.5 years (range 25-89 years) who had colonoscopy for EFTR. In three patients EFTR was not feasible because the lesions were too large. Of the remaining 67 patients, 52 had recurrent adenomas, 10 had high-grade intraepithelial neoplasia or mucosal carcinoma and five had a subepithelial lesion. Resection was technically successful in 65 patients (97.0%). Histologically complete resection (R0) was achieved in 59/65 patients (90.8%). The R0 resection rate was lower for lesions > 20 mm (86.5%) versus lesions ≤ 20 mm (92.9%). The total complication rate was 14.9%: there was one major complication (perforation of sigmoid colon), while all other complications were minor. CONCLUSIONS: EFTR yields excellent resection rates for benign recurrent adenomas with non-lifting sign, advanced histopathological findings or submucosal lesions when the procedure is performed in experienced hands and for the correct indication. Thus, surgery can be avoided in many cases. For all lesions the risk of R1 resection goes up with the size of the lesion and careful patient selection is mandatory.

[A 34-year-old patient with retropharyngeal tendinitis]. / Ein 34-jähriger Patient mit retropharyngealer Tendinitis.

This article reports the case of a 34-year-old male patient presenting with neck pain, massive pressure pain of the neck muscles and limited cervical rotational mobility. Laboratory tests showed elevated levels for markers of inflammation. Computed tomography (CT) and magnetic resonance imaging (MRI) detected a retropharyngeal tendinitis of the longus cervicis muscle. This rare clinical entity is probably responsible for a high number of unreported cases. A CT scan, which can identify prevertebral edema and light calcification inferior to the ventral aspect of the second cervical vertebra, was previously the gold standard. Meanwhile, MRI scans now show a higher sensitivity in the detection of prevertebral edema. The first line treatment is the administration of non-steroidal anti-inflammatory drugs (NSAIDs).

[Successful pembrolizumab therapy in metastasized adenosquamous carcinoma of the colon]. / Erfolgreiche Pembrolizumab-Therapie bei metastasiertem adenosquamösem Karzinom des Kolons.

Adenosquamous carcinoma (ASqC) is an exceedingly rare subtype of colorectal cancer without any known special guidelines for treatment. The biological behaviour and molecular background are widely unknown, although a few case studies report a worse prognosis compared to ordinary colorectal adenocarcinoma. We herein report for the first time the successful immune checkpoint inhibitor therapy in a 40-year-old patient suffering from metastasized right-sided colonic ASqC with unique molecular features, after having previously progressed under standard chemotherapy.

Distribution of clinically relevant antibiotic resistance genes in Lake Tai, China.

Lake Tai is China's third largest freshwater lake and an important water resource for agriculture, industrial sectors, and as drinking water for several large cities. In this study, the occurrence of five antibiotic resistance genes (sul1, blaTEM, blaNDM-1, blaCTX-M-32, mcr-1) was investigated in water and sediment samples collected from Lake Tai. Antibiotic resistances are currently increasing, posing a significant threat to public health. The sulfonamide resistance gene sul1 was highly abundant in all analyzed water and sediment samples. In addition, the two ß-lactamase genes blaTEMand blaNDM-1 - encoding clinically relevant antibiotic resistances - were detected in 67.1 and 7.3% of the water samples and in 70.7 and 15.4% of the sediment samples. The third ß-lactamase gene, blaCTX-M-32, was only detected in water samples (13.4%), while the colistin resistance gene mcr-1 was not detected in any of the samples. No significant variations between different sampling sites or time points could be observed. The investigation of drinking water treatment at Lake Tai, using lake water as influent, showed a significant reduction of the antibiotic resistance genes through the treatment process. Microbial source tracking showed only low fecal contamination by humans, ruminants, and pigs, indicating the relevance of other sources such as fish farms. Overall, our results provide important insights into the occurrence and abundance of antibiotic resistance genes in the Lake Tai water system and their elimination via drinking water treatment.

Mapping the electric field distribution of tightly focused cylindrical vector beams with gold nanorings.

In this paper gold nanorings (NRs) are applied as particularly well-suited sensing elements for mapping the radially symmetric electric fields in the high numerical aperture focus of cylindrical vector beams. The optical properties of gold nanorings are analyzed by a combination of extinction and single particle dark field spectroscopy as well as confocal photoluminescence (PL) imaging. The results are compared to numerical calculations. The in-plane components in the focus of the cylindrical vector beams are estimated through the PL intensity distributions of the NRs. The optimum overlap between the structure and excitation is visualized by a narrow centre spot in the far-field PL scan.

Fluoride-fiber-based side-pump coupler for high-power fiber lasers at 2.8 µm.

A side-pump coupler made of fluoride fibers was fabricated and tested. The tested device had a coupling efficiency of 83% and was driven with an incident pump power of up to 83.5 W, demonstrating high-power operation. Stable laser output of 15 W at a wavelength of around 2.8 µm was achieved over 1 h when using an erbium-doped double-clad fiber as the active medium. To the best of our knowledge, this is the first time a fluoride-glass-fiber-based side-pump coupler has been developed. A test with two devices demonstrated further power scalability.