Acute pancreatitis: 31-Year trends in incidence and mortality - A Danish population-based cohort study.

BACKGROUND: Objectives: Increasing incidence rates and declining mortality rates have made acute pancreatitis a common cause of hospitalization. We aimed to examine 31-year trends in first-time hospitalization for acute pancreatitis, the subsequent short-term and long-term mortality, and the prognostic impacts of age, sex, and comorbidity. METHODS: In this nationwide Danish population-based cohort study of 47,711 incident cases, we computed the annual sex-specific age-standardized incidence rates of acute pancreatitis for 1988-2018. Among patients with incident hospitalization for acute pancreatitis, we computed sex-specific 30-day and 31-365-day mortality rates, stratified them, and performed proportional-hazards regression to estimate mortality rate ratios adjusted for sex, age, and comorbidity, measured by Charlson Comorbidity Index categories. RESULTS: From 1988 to 2018, the standardized incidence rate of acute pancreatitis per 100,000 person-years increased by 29% for men (28.8-37.0%) and by 148% for women (15.7-38.9%). Among patients with pancreatitis, the 30-day mortality declined from 10.0% in those diagnosed in 1988-1992 to 6.3% for those diagnosed in 2013-2017. The corresponding 31-365 day mortality increased from 5.5% to 6.0%. In comparing periods 1988-1992 and 2013-17, the adjusted 30-day mortality rate ratio was 0.36 (95% confidence interval: 0.32-0.41) and the adjusted 31-365 day mortality rate ratio was 0.64 (95% confidence interval: 0.56-0.74). Comorbidity was a strong predictor of mortality among patients with pancreatitis. CONCLUSIONS: Over the 31 years of observations, annual rates of acute pancreatitis more than doubled among women, converging with those among men. The comorbidity burden was a strong prognostic factor for short and long-term mortality. Treatments for acute pancreatitis should focus on existing comorbidities.

Identifying Valid Algorithms for Number of Lines of Anti-Neoplastic Therapy in the Danish National Patient Registry Among Patients with Advanced Ovarian, Gastric, Renal Cell, Urothelial, and Non-Small Cell Lung Cancer Attending a Danish University Hospital.

PURPOSE: To develop algorithms to identify number of lines of anti-neoplastic therapy per patient based on the Danish National Patient Registry (DNPR) and identify which algorithm has the highest percentage agreement with a reference standard of documentation in medical records. PATIENTS AND METHODS: We included 179 patients diagnosed between January 1, 2012, and December 31, 2016, with stage II, III, or IV urothelial cell carcinoma or stage III or IV epithelial ovarian cancer, gastric adenocarcinoma, renal cell carcinoma, or non-small cell lung cancer (NSCLC). We developed two algorithms for number of lines of anti-neoplastic therapy based on dates and treatment codes (eg, "treatment with cisplatin" or "cytostatic treatment") in the DNPR. First, to denote a change in line of therapy the "Time-based algorithm" used the number of days between consecutive administrations. Second, the "Drug-based algorithm" used information on drug names if available or the number of days between consecutive administrations if no drug names were specified. We calculated the percentage agreement between the algorithms setting the number of allowed days between consecutive administrations from 28 to 50 and the reference standard - information on anti-neoplastic therapy drugs abstracted from medical records and subsequently coded according to lines of anti-neoplastic therapy. RESULTS: For the "Time-based algorithm", the highest percentage agreement with the reference standard was found when using <45 days between consecutive administrations (67.6%; 95% CI: 60.1-73.8%). However, the percentage agreement was higher for the "Drug-based algorithm" using <45 days between consecutive administrations for registrations where the drug name was unspecified (90.5%; 95% CI: 85.0-93.7%). CONCLUSION: The algorithm for number of lines of anti-neoplastic therapy that had the highest percentage agreement with the reference standard (medical records) incorporated both registration of specific drug names and <45 days between consecutive administrations if the drug name was unspecified in routinely recorded data from DNPR.

Hospitalization for hypoglycaemia in people with diabetes in Denmark, 1997-2017: Time trends in incidence and HbA1c and glucose-lowering drug use before and after hypoglycaemia.

OBJECTIVE: To assess incidence trends of first hospitalization for hypoglycaemia in Denmark and to examine HbA1c levels and glucose-lowering drug use before and after hospitalization among individuals with type 1 or type 2 diabetes. RESEARCH DESIGN AND METHODS: We performed a population-based study linking diagnosis, prescription and laboratory data. Standardized incidence of first hospitalization for hypoglycaemia in Denmark was assessed for each calendar year 1997-2017. HbA1c and glucose-lowering drug use was compared with age- and sex-matched diabetes comparisons without hospitalization for hypoglycaemia. RESULTS: The annual age- and sex-standardized incidence rate of first hospitalization for hypoglycaemia per 100,000 person-years increased during 1997-2003 (from 17.7 to 30.3 per 100,000 person-years), remained stable until 2010 (30.4) and gradually declined until 2017 (22.0). During this period, we identified 3,479 people with type 1 diabetes and 15,329 people with type 2 diabetes experiencing first hospitalization for hypoglycaemia. Both diabetes groups experienced a mean HbA1c decrease of ~12%-15% in the months preceding first hospitalization, followed by a gradually increasing HbA1c afterwards. People with type 1 diabetes and hospitalization used similar insulin therapies as those without hospitalization. People with type 2 diabetes and hospitalization more often received insulin (55%) than comparisons (45%), and 45% discontinued insulin or stopped all glucose-lowering therapy after first hospitalization. CONCLUSIONS: Incidence of hospitalizations for hypoglycaemia has declined by one fourth the last decade in the Danish population. A HbA1c decrease precedes first hospitalization for hypoglycaemia in individuals with diabetes, and profound changes in glucose-lowering drug therapy for type 2 diabetes occur after hospitalization.

Systematic Review of Oral Combination Therapy for Erectile Dysfunction When Phosphodiesterase Type 5 Inhibitor Monotherapy Fails.

INTRODUCTION: On-demand phosphodiesterase type 5 inhibitor (PDE5i) monotherapy is a first-line treatment for erectile dysfunction (ED), but 30%-40% of patients exhibit little or no response. The success rate of alprostadil therapy is high in these patients, but this treatment requires painful intracavernosal injection. AIM: To systematically review the efficacy and safety of second-line oral pharmacologic combination therapies of ED when PDE5i monotherapy fails. METHODS: PubMed and Embase were searched to identify reports providing quantitative data on the treatment of ED in patients failing PDE5i monotherapy. MAIN OUTCOME MEASURES: The measures of erectile function were the International Index of Erectile Function (IIEF) and the Erectile Function Domain (EFD). RESULTS: Chronic treatment with the PDE5i tadalafil alone or in combination with sildenafil on demand showed similar IIEF-5 score improvements. None of the 3 randomized controlled trials (RCTs) in patients who had failed PDE5i monotherapy found a superior effect on IIEF scores from the combination of androgen plus PDE5i compared with PDE5i monotherapy. Combination therapy with androgen supplementation and PDE5i appears safe. In 1 RCT, combination therapy with PDE5i and an α1-adrenoceptor antagonist was not superior to PDE5i monotherapy. Six other studies, each with a different combination of PDE5i and another drug (eg, metformin, folic acid, 5-alpha-reductase inhibitors), were identified, but further research is required to investigate their efficacy in treating ED. CONCLUSION: For ED, chronic treatment with low-dose PDE5i can be attempted when standard on-demand regimens fail. Combination therapy with androgen supplementation and a PDE5i appears to be safe. The combination of an α1-adrenoceptor antagonist and PDE5i shows no advantageous effect on ED compared with PDE5i monotherapy. The efficacy of combining PDE5i with metformin, folic acid, or 5-alpha-reductase inhibitors is uncertain and requires further research. There is an unmet need for oral treatment of ED in nonresponders to PDE5i treatment. Munk NE, Knudsen JS, Comerma-Steffensen S, et al. Systematic Review of Oral Combination Therapy for Erectile Dysfunction When Phosphodiesterase Type 5 Inhibitor Monotherapy Fails. Sex Med Rev 2019;7:430-441.

Different mechanisms involved in liraglutide and glucagon-like peptide-1 vasodilatation in rat mesenteric small arteries.

BACKGROUND AND PURPOSE: Glucagon-like peptide-1 (GLP-1) is an incretin hormone that regulates insulin biosynthesis and secretion in a glucose-dependent manner and has been reported to induce vasodilatation. Here, we examined the possible vasorelaxant effect of GLP-1 and its underlying mechanisms. EXPERIMENTAL APPROACH: Rat mesenteric arteries (diameter ≈ 200-400 µm) and human s.c. arteries were mounted in microvascular myographs for isometric tension recordings. The effect of GLP-1 on vascular responses was examined under normoglycaemic conditions and at high glucose concentrations. KEY RESULTS: In rat mesenteric arteries and human s.c. arteries without branches, physiological concentrations (1-100 nM) of GLP-1(7-36) and liraglutide failed to cause relaxation or affect contractions evoked by electrical field stimulation. In contrast to GLP-1(7-36), liraglutide induced relaxations antagonized by the GLP-1 receptor antagonist, exendin-(9-39), in branched mesenteric arteries. In contrast to liraglutide, GLP-1 leftward shifted the concentration relaxation curves for bradykinin in s.c. arteries from patients with peripheral arterial disease, an effect resistant to exendin-(9-39). Under normoglycaemic conditions, neither GLP-1 nor liraglutide affected ACh relaxation in rat mesenteric arteries. In arteries exposed to 40 mM glucose, GLP-1, in contrast to liraglutide, potentiated ACh-induced relaxation by a mechanism that was not antagonized by exendin-(9-39). GLP-1 decreased superoxide levels measured with dihydroethidium in rat mesenteric arteries exposed to 40 mM glucose. CONCLUSIONS AND IMPLICATIONS: GLP-1 receptors are involved in the liraglutide-induced relaxation of branched arteries, under normoglycaemic conditions, while GLP-1 inhibition of vascular superoxide levels contributes to GLP-1 receptor-independent potentiation of endothelium-dependent vasodilatation in hyperglycaemia.

Novel selective PDE type 1 inhibitors cause vasodilatation and lower blood pressure in rats.

BACKGROUND AND PURPOSE: The PDE enzymes (PDE1-11) hydrolyse and thus inactivate cyclic nucleotides and are important in the regulation of the cardiovascular system. Here,we have investigated the effects on the cardiovascular system, of two novel selective PDE1 inhibitors, Lu AF41228 and Lu AF58027. EXPERIMENTAL APPROACH: We used rat mesenteric small arteries (internal diameters of 200-300 µm), RT-PCR and measured isometric wall tension. Effects of Lu AF41228 and Lu AF58027 on heart rate and BP were assessed in both anaesthetized and conscious male rats. KEY RESULTS: Nanomolar concentrations of Lu AF41228 and Lu AF58027 inhibited PDE1A, PDE1B and PDE1C enzyme activity, while micromolar concentrations were required to observe inhibitory effects at other PDEs. RT-PCR revealed expression of PDE1A, PDE1B and PDE1C in rat brain, heart and aorta, but only PDE1A and PDE1B in mesenteric arteries. In rat isolated mesenteric arteries contracted with phenylephrine or U46619, Lu AF41228 and Lu AF58027 induced concentration-dependent relaxations which were markedly reduced by inhibitors of guanylate cyclase, ODQ, and adenylate cyclase, SQ22536, and in preparations without endothelium. In anaesthetized rats, Lu AF41228 and Lu AF58027 dose-dependently lowered mean BP and increased heart rate. In conscious rats with telemetric pressure transducers, repeated dosing with Lu AF41228 lowered mean arterial BP 10-15 mmHg and increased heart rate. CONCLUSIONS AND IMPLICATIONS: These novel PDE1 inhibitors induce vasodilation and lower BP, suggesting a potential use of these vasodilators in the treatment of hypertension and vasospasm.