Progesterone concentrations on blastocyst transfer day in modified natural cycle frozen embryo transfer cycles.

RESEARCH QUESTION: Are serum progesterone concentrations on the day of modified natural cycle (mNC) frozen blastocyst transfer (FET) without luteal phase support (LPS) associated with clinical pregnancy rate (CPR)? DESIGN: Data were collected between January 2019 and October 2022 as a sub-study of an ongoing randomized controlled trial assessing pregnancy outcomes in mNC-FET. The sub-study included all women (n = 209) randomized to mNC-FET without LPS at the time of data extraction. Participants were aged 18-41 years, had regular menstrual cycles and underwent mNC-FET treatment with single-blastocyst transfer. Associations between the serum progesterone concentration on the day of blastocyst transfer and CPR, pregnancy rate and pregnancy loss rate (PLR) were examined between groups with low and higher progesterone concentrations using the 25th and 10th percentiles as cut-offs. Multivariate logistic regression analyses were performed to adjust for potential confounding factors. RESULTS: Progesterone concentrations on the day of blastocyst transfer in mNC-FET without LPS ranged from 4.9 to 91.8 nmol/l, with the 25th and 10th percentiles at 29.0 nmol/l and 22.5 nmol/l, respectively. Serum progesterone concentrations did not differ between women with or without a clinical pregnancy (mean [SD] 38.5 [14.0] versus 36.8 [12.4] nmol/l; P = 0.350). Furthermore, the CPR, pregancy rate and PLR were similar in women with low or high progesterone concentrations when using the 25th or the 10th progesterone percentile as cut-off. Multivariate regression analyses showed no association between progesterone concentrations and CPR. CONCLUSIONS: No association was found between progesterone concentration on the day of blastocyst transfer and pregnancy outcome in women undergoing mNC-FET without progesterone LPS.

Elevated Levels of Interleukin-1ß and Interleukin-10 Are Associated With Faster Lung Function Decline in People With Well-Treated Human Immunodeficiency Virus.

BACKGROUND: People with human immunodeficiency virus (PWH) have an increased risk of chronic lung diseases and chronic inflammation. We aimed to investigate if inflammatory markers and monocyte activation are associated with faster lung function decline in PWH. METHODS: We included 655 PWH from the Copenhagen Comorbidity in HIV Infection (COCOMO) Study. Eligible participants were aged ≥25 years and had 2 spirometries separated by >2 years. Inflammatory markers (interleukin [IL]-1ß, IL-2, IL-6, IL-10, tumor necrosis factor-α, and interferon-γ) were measured at baseline by Luminex, and soluble CD14 and soluble CD163 by enzyme-linked immunosorbent assay. Using linear mixed models, we investigated whether elevated cytokine levels were associated with faster lung function decline. RESULTS: The majority of PWH were males (85.2%) with undetectable viral replication (95.3%). We found a faster decline in forced expiratory volume in 1 second (FEV1) in PWH with elevated IL-1ß and IL-10, with an additional decline of 10.3 mL/year (95% confidence interval [CI], 2.1-18.6; P = .014) and 10.0 mL/year (95% CI, 1.8-18.2; P = .017), respectively. We found no interaction between smoking and IL-1ß or IL-10 on FEV1 decline. CONCLUSIONS: Elevated IL-1ß and IL-10 were independently associated with faster lung function decline in PWH, suggesting that dysregulated systemic inflammation may play a role in the pathogenesis of chronic lung diseases.

Expression of Secretin and its Receptor Along the Intestinal Tract in Type 2 Diabetes Patients and Healthy Controls.

CONTEXT: The hormone secretin (SCT) is released from intestinal S cells and acts via the SCT receptor (SCTR). Circulating SCT levels increase after Roux-en-Y gastric bypass surgery and have been associated with massive weight loss and high remission rates of type 2 diabetes (T2D) linked to these operations. Exogenous SCT was recently shown to reduce ad libitum food intake in healthy volunteers. OBJECTIVE: To understand SCT biology and its potential role in T2D pathophysiology, we examined the intestinal mucosal expression profile of SCT and SCTR and evaluated the density of S cells along the intestinal tract of individuals with T2D and healthy controls. METHODS: Using immunohistochemistry and messenger RNA (mRNA) sequencing, we analyzed intestinal mucosa biopsies sampled along the small intestine at 30-cm intervals and from 7 well-defined anatomical sites along the large intestine (during 2 sessions of double-balloon enteroscopy) in 12 individuals with T2D and 12 healthy controls. RESULTS: Both groups exhibited a progressive and similar decrease in SCT and SCTR mRNA expression and S-cell density along the small intestine, with reductions of 14, 100, and 50 times, respectively, in the ileum compared to the duodenum (used as reference). Negligible amounts of SCTR and SCT mRNA, as well as low S-cell density, were found in the large intestine. No significant differences were observed between the groups. CONCLUSION: SCT and SCTR mRNA expression and S-cell density were abundant in the duodenum and decreased along the small intestine. Very low SCT and SCTR mRNA levels and S-cell numbers were observed in the large intestine, without aberrations in individuals with T2D compared to healthy controls.

Separate and combined effects of long-term GIP and GLP-1 receptor activation in patients with type 2 diabetes: a structured summary of a study protocol for a double-blind, randomised, placebo-controlled clinical trial.

INTRODUCTION: Due to reports of severely reduced insulinotropic effect of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) in type 2 diabetes (T2D), GIP has not been considered therapeutically viable. Recently, however, tirzepatide, a novel dual incretin receptor agonist (activating the GIP receptor and the glucagon-like peptide 1 (GLP-1) receptor) has demonstrated greater glucose and body weight-lowering properties as compared to GLP-1 receptor agonist therapy. The contribution of GIP receptor activation to effects of tirzepatide remains unknown. We will evaluate the glucose-lowering effect of exogenous GIP in the context of pharmacological GLP-1 receptor activation in patients with T2D. METHODS AND ANALYSIS: In this randomised, double-blind, four-arm parallel, placebo-controlled trial, 60 patients with T2D will be included (18-74 of age; on diet and exercise and/or metformin therapy only; glycated haemoglobin 6.5-10.5% (48-91 mmol/mol)). Participants will be randomised to an 8-week run-in period with subcutaneous (s.c.) placebo or semaglutide injections once-weekly (0.5 mg). Participants will then be randomised to 6 weeks' add-on treatment with continuous s.c. placebo or GIP infusion (16 pmol/kg/min). The primary endpoint is change in mean glucose levels (assessed by 14-day continuous glucose monitoring) from the end of the run-in period to end of trial. ETHICS AND DISSEMINATION: The present study was approved by the Regional Committee on Health Research Ethics in the Capitol Region of Denmark (identification no. H-20070184) and by the Danish Medicines Agency (EudraCT no. 2020-004774-22). All results, positive, negative and inconclusive, will be disseminated at national and/or international scientific meetings and in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBERS: NCT05078255 and U1111-1259-1491.

Reduction of cardiac adipose tissue volume with short-term empagliflozin treatment in patients with type 2 diabetes: A substudy from the SIMPLE randomized clinical trial.

OBJECTIVE: Ectopic accumulation of cardiac adipose tissue volume (CAT) has been associated with cardiac remodelling and cardiac dysfunction in type 2 diabetes and may be a future therapeutic target. In this substudy from the SIMPLE-trial, we investigated short-term empagliflozin therapy's effects on CAT in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Between 4 April 2017 and 11 May 2020, we randomized 90 patients with type 2 diabetes and established or high risk of cardiovascular disease to 25 mg empagliflozin or placebo for 13 weeks. The substudy focused on change in CAT evaluated by images acquired during 82 Rubidium-positron emissions tomography/computed tomography. The analysis included 78 patients who had at least one scan. Furthermore, we report on the relation to the concurrent effects on left ventricular mass, end-diastolic volume and end-systolic volume, body composition and glucometabolic status. RESULTS: Mean ± SD baseline CAT was 258.5 ± 117.9 ml. Empagliflozin reduced CAT after 13 weeks by 12.41 ml [95% CI (-23.83 to -0.99), p = .034] as compared with placebo. Similarly, left ventricular mass [-5.16 g, 95% CI (-8.80 to -1.52), p = .006], end-diastolic volume and end-systolic volume decreased with empagliflozin. In addition, significant improvements were observed in body composition, with reduced total fat mass, and in measures of glucose and lipid metabolism. However, no correlation was observed between changes in CAT and changes in cardiac parameters and change in CAT appeared mediated primarily by concurrent change in weight. CONCLUSIONS: Empagliflozin provides an early reduction of CAT; however, no association was observed with concurrent changes in cardiac volumetrics.

How to Report Data on Bilateral Procedures and Other Issues with Clustered Data: The CLUDA Reporting Guidelines.

BACKGROUND: Research in plastic surgery often includes bilateral procedures. This gives rise to issues with clustered data. Clustering is when individual data points within a data set are internally related. However, many authors do not account for clustering within their data, which can lead to incorrect statistical conclusions. METHODS: In February of 2020, the authors searched PubMed to investigate the prevalence of reporting issues with bilateral breast procedures in plastic surgery literature. The review focused on breast surgery, as it often involves bilateral procedures and, therefore, clustering. Based on the review, the authors developed guidelines for how to identify and address clustered data. The guidelines were modified by a multidisciplinary group consisting of a biostatistician with expertise in clustered data at the Section of Biostatistics, University of Copenhagen, and three doctors (M.D.s and Ph.D.s) with expertise in statistical analysis and scientific methodology from the Copenhagen University Hospital, Rigshospitalet. RESULTS: A total of 113 studies were included in the review. Seventy-five studies (66 percent) contained clustered data, but only eight studies (11 percent) took clustering into account in the statistical analysis. These results were used to develop the Clustered Data, or CLUDA, reporting guidelines which consist of two sections: one to identify clustering and one for reporting and analyzing clustered data. CONCLUSIONS: Clustered data are abundant in plastic surgery literature. The authors propose using the Clustered Data reporting guidelines to identify and report clustered data and consulting with a biostatistician when designing a study.

The glucagon receptor antagonist LY2409021 has no effect on postprandial glucose in type 2 diabetes.

OBJECTIVE: Type 2 diabetes (T2D) pathophysiology includes fasting and postprandial hyperglucagonemia, which has been linked to hyperglycemia via increased endogenous glucose production (EGP). We used a glucagon receptor antagonist (LY2409021) and stable isotope tracer infusions to investigate the consequences of hyperglucagonemia in T2D. DESIGN: A double-blinded, randomized, placebo-controlled crossover study was conducted. METHODS: Ten patients with T2D and ten matched non-diabetic controls underwent two liquid mixed meal tests preceded by single-dose administration of LY2409021 (100 mg) or placebo. Double-tracer technique was used to quantify EGP. Antagonist selectivity toward related incretin receptors was determined in vitro. RESULTS: Compared to placebo, LY2409021 lowered the fasting plasma glucose (FPG) from 9.1 to 7.1 mmol/L in patients and from 5.6 to 5.0 mmol/L in controls (both P < 0.001) by mechanisms involving reduction of EGP. Postprandial plasma glucose excursions (baseline-subtracted area under the curve) were unaffected by LY2409021 in patients and increased in controls compared to placebo. Glucagon concentrations more than doubled during glucagon receptor antagonism. The antagonist interfered with both glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide receptors, complicating the interpretation of the postprandial data. CONCLUSIONS: LY2409021 lowered FPG concentrations but did not improve postprandial glucose tolerance after a meal in patients with T2D and controls. The metabolic consequences of postprandial hyperglucagonemia are difficult to evaluate using LY2409021 because of its antagonizing effects on the incretin receptors.

Assessing Light and Energy-Based Therapy by Optical Coherence Tomography and Reflectance Confocal Microscopy: A Randomized Trial of Photoaged Skin.

BACKGROUND AND OBJECTIVES: Image-guided quantitative and semi-quantitative assessment of skin can potentially evaluate treatment efficacy. Optical coherence tomography (OCT) and reflectance confocal microscopy (RCM) are ideal for this purpose. This study assessed clinically relevant statistical changes in RCM and OCT features in photoaged skin after light and energy-based therapy. METHODS: Novel statistical analyses were performed using OCT and RCM data collected during a previously published trial: a 12-week study of female décolleté skin randomized to four areas treated with thulium laser (L), photodynamic therapy (PDT), combined L-PDT, and control. Eight semi-quantitative RCM scores of photodamage and OCT measurements of skin roughness, blood flow, and epidermal thickness (ET) were evaluated and compared to dermoscopy and clinical skin scores. In statistical analysis, estimated treatment difference (ETD) was calculated. RESULTS: Twelve women with moderate to severe photodamage were included. RCM and OCT data demonstrated a trend towards rejuvenation of epidermis with increased ET, changes in skin surface, and improved honeycomb pattern in RCM. In angiographic OCT, non-significant changes towards more regular capillary meshes were shown, which matched a decline in appearance of gross telangiectasias in dermoscopy. Improved skin tone after laser and L-PDT was identified in RCM, showing less edged papillae in 36% and 45%, and lentigo number declined in 55% of patients after treatments in dermoscopy. Based on clinical scores, L-PDT provided the greatest clinical improvement, which corresponded to superior ETD outcomes in ET and edged papillae shown in OCT and RCM, respectively. CONCLUSION: Objective OCT and RCM assessment of skin rejuvenation was demonstrated in this study. Importantly, image-based improvements corresponded to favorable clinical skin scores and fewer photoaging characteristics in dermoscopy. Importantly, most changes did not reach statistical significance, prompting further studies and emphasizing the modest value of non-randomized, non-blinded anti-aging trials.

Prednisolone and Ketorolac vs Ketorolac Monotherapy or Sub-Tenon Prophylaxis for Macular Thickening in Cataract Surgery: A Randomized Clinical Trial.

IMPORTANCE: The choice of anti-inflammatory prophylaxis parallel to cataract surgery is important for patient safety and successful outcome of surgery, but which regimen to choose is contested. OBJECTIVES: To determine whether a combination of prednisolone and nonsteroidal anti-inflammatory drug (NSAID) eye drops was superior in preventing increased central macular thickness (central subfield thickness [CST]) after uncomplicated cataract surgery compared with NSAID monotherapy and sub-Tenon capsule depot (dropless surgery), and to test whether preoperative initiation of eye drop treatment was superior to initiation on the day of surgery. DESIGN, SETTING, AND PARTICIPANTS: This investigator-driven, single-center, randomized clinical trial with masked statistical analyses enrolled patients at the Department of Ophthalmology, Rigshospitalet Glostrup, Glostrup, Denmark, from February 1, 2018, to August 15, 2019. Follow-up was completed December 18, 2019. Participants included low-risk patients undergoing phacoemulsification for age-related cataract by an experienced surgeon (1 eye per participant). Data were analyzed from February 17 to June 15, 2020. INTERVENTIONS: Participants scheduled for cataract removal were randomized to 1 of 5 anti-inflammatory prophylactic regimens: eye drops with a combination of prednisolone, 1%, and ketorolac tromethamine, 0.5%, with or without preoperative initiation (preoperative prednisolone plus NSAID [control] and postoperative prednisolone plus NSAID groups), ketorolac monotherapy with or without preoperative initiation (preoperative and postoperative NSAID groups), or sub-Tenon depot of dexamethasone phosphate (sub-Tenon group). Eye drops were administered 3 times per day until 3 weeks postoperatively. MAIN OUTCOMES AND MEASURES: CST 3 months postoperatively. RESULTS: A total of 470 participants (mean [SD] age, 72.2 [7.0] years; 290 women [61.7%]) with 94 participants in each group were included in the analysis. Three months after surgery, the mean CST was 250.7 (95% CI, 247.6-253.7) µm in the preoperative prednisolone plus NSAID group, 250.7 (95% CI, 247.8-253.7) µm in the postoperative prednisolone plus NSAID group, 251.3 (95% CI, 248.2-254.4) µm in the preoperative NSAID group, 249.2 (95% CI, 246.2-252.3) µm in the postoperative NSAID group, and 255.2 (95% CI, 252.0-258.3) µm in the sub-Tenon group. There were no significant differences in CST or visual acuity compared with control and no differences between preoperative and postoperative groups, but 47 of 83 participants (56.6%) in the sub-Tenon group needed additional anti-inflammatory treatment. CONCLUSIONS AND RELEVANCE: No differences in CST or visual acuity were detected between the combination of prednisolone and NSAID eye drops vs NSAID monotherapy or sub-Tenon dexamethasone depot, although more than one-half of patients in the sub-Tenon arm received additional anti-inflammatory treatment. Initiating prophylaxis 3 days preoperatively was not superior to initiation on the day of surgery. Monotherapy with NSAIDs may be preferred in uncomplicated cataract surgery. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03383328.

Diagnostic accuracy and clinical impact of [18F]FET PET in childhood CNS tumors.

BACKGROUND: Central nervous system (CNS) tumors cause the highest death rates among childhood cancers, and survivors frequently have severe late effects. Magnetic resonance imaging (MRI) is the imaging modality of choice, but its specificity can be challenged by treatment-induced signal changes. In adults, O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET) PET can assist in interpreting MRI findings. We assessed the clinical impact and diagnostic accuracy of adding [18F]FET PET to MRI in children with CNS tumors. METHODS: A total of 169 [18F]FET PET scans were performed in 97 prospectively and consecutively included patients with known or suspected childhood CNS tumors. Scans were performed at primary diagnosis, before or after treatment, or at relapse. RESULTS: Adding [18F]FET PET to MRI impacted clinical management in 8% [95% confidence interval (CI): 4%-13%] of all scans (n = 151) and in 33% [CI: 17%-53%] of scans deemed clinically indicated due to difficult decision making on MRI alone (n = 30). Using pathology or follow-up as reference standard, the addition of [18F]FET PET increased specificity (1.00 [0.82-1.00] vs 0.48 [0.30-0.70], P = .0001) and accuracy (0.91 [CI: 0.87-0.96] vs 0.81 [CI: 0.75-0.89], P = .04) in 83 treated lesions and accuracy in 58 untreated lesions (0.96 [CI: 0.91-1.00] vs 0.90 [CI: 0.82-0.92], P < .001). Further, in a subset of patients (n = 15) [18F]FET uptake correlated positively with genomic proliferation index. CONCLUSIONS: The addition of [18F]FET PET to MRI helped discriminate tumor from non-tumor lesions in the largest consecutive cohort of pediatric CNS tumor patients presented to date.

Effect of anti-inflammatory regimen on early postoperative inflammation after cataract surgery.

PURPOSE: To investigate whether a combination of topical nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids were superior in controlling early postoperative inflammation after cataract surgery compared with topical NSAIDs alone and with dropless surgery where a sub-Tenon depot of steroid was placed during surgery. SETTING: Department of Ophthalmology, Rigshospitalet-Glostrup, Denmark. DESIGN: Prospective randomized controlled trial with masked statistical analyses. METHODS: Patients undergoing phacoemulsification for age-related cataract were randomized to 1 of 5 regimens: ketorolac and prednisolone eyedrops combined (Pred+NSAID-Pre [control group] and Pred+NSAID-Post group) vs ketorolac monotherapy (NSAID-Pre and NSAID-Post groups) vs sub-Tenon depot of dexamethasone (dropless group). Drops were used until 3 weeks postoperatively, starting 3 days preoperatively in the Pre groups and on the day of surgery in the Post groups. Aqueous flare was measured at baseline and 3 days postoperatively. RESULTS: Four hundred fifty-six participants, with a mean age of 72.1 (SD 7.0) years and 283 (62%) women, were included. Flare increased significantly more in the dropless group compared with the control group (Pred+NSAID-Pre), but none of the other groups differed significantly from the control group. Intraocular pressure decreased in all groups but significantly less in groups receiving prednisolone eyedrops (Pred+NSAID-Pre and Pred+NSAID-Post groups) compared with NSAID monotherapy and dropless groups. No differences in postoperative visual acuity were found compared with the control group. CONCLUSIONS: No differences were found between groups randomized to NSAID monotherapy or combination of NSAID and steroid in controlling early inflammation after cataract surgery, but sub-Tenon depot of dexamethasone was less efficient. Initiating prophylactic eyedrops prior to surgery did not influence early postoperative anterior chamber inflammation.

Gut Mucosal Gene Expression and Metabolic Changes After Roux-en-Y Gastric Bypass Surgery.

OBJECTIVE: Changes in the secretion of gut-derived peptide hormones have been associated with the metabolic benefits of Roux-en-Y gastric bypass (RYGB) surgery. In this study, the effects of RYGB on anthropometrics, postprandial plasma hormone responses, and mRNA expression in small intestinal mucosa biopsy specimens before and after RYGB were evaluated. METHODS: In a cross-sectional study, 20 individuals with obesity undergoing RYGB underwent mixed meal tests and upper enteroscopy with retrieval of small intestinal mucosa biopsy specimens 3 months before and after surgery. Concentrations of circulating gut and pancreatic hormones during mixed meal tests as well as full mRNA sequencing of biopsy specimens were evaluated. RESULTS: RYGB-induced improvements of body weight and composition, insulin resistance, and circulating cholesterols were accompanied by significant changes in postprandial plasma responses of pancreatic and gut hormones. Global gene expression analysis of biopsy specimens identified 2,437 differentially expressed genes after RYGB, including changes in genes that encode prohormones and G protein-coupled receptors. CONCLUSIONS: RYGB affects the transcription of a wide range of genes, indicating that the observed beneficial metabolic effects of RYGB may rely on a changed expression of several genes in the gut. RYGB-induced changes in the expression of genes encoding signaling peptides and G protein-coupled receptors may disclose new gut-derived treatment targets against obesity and diabetes.

Efficacy and safety of meal-time administration of short-acting exenatide for glycaemic control in type 1 diabetes (MAG1C): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: In type 2 diabetes, long-acting GLP-1 receptor agonists lower fasting plasma glucose and improve glycaemic control via their insulinotropic and glucagonostatic effects. In type 1 diabetes, their efficacy as an add-on treatment to insulin therapy is modest. Short-acting GLP-1 receptor agonists also lower postprandial glucose excursions in type 2 diabetes by decelerating gastric emptying rate. We aimed to test the efficacy of a short-acting GLP-1 receptor agonist in type 1 diabetes. METHODS: In the single-centre, parallel-group, randomised, double-blind, placebo-controlled MAG1C trial, patients with type 1 diabetes on multiple daily injection therapy aged 18 years and older with HbA1c 59-88 mmol/mol (7·5-10·0%) and a BMI of more than 22·0 kg/m2 were randomly assigned (1:1) through a computer-generated randomisation list to preprandial subcutaneous injection of 10 µg exenatide (Byetta) or placebo three times daily for 26 weeks as an add-on treatment to usual insulin therapy. Clinically assessed insulin titration was done by study staff. Participants and investigators were masked to treatment allocation. The primary endpoint was between-group difference in HbA1c after 26 weeks. Data were analysed with a baseline-adjusted linear mixed model in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03017352, and is completed. FINDINGS: Between Jan 4, 2017, and Jan 16, 2019, 108 participants were randomly assigned, 54 to exenatide and 54 to placebo; 23 participants discontinued treatment (17 in the exenatide group and six in the placebo group). From a baseline-adjusted mean of 66·4 mmol/mol (95% CI 64·9-67·8 [8·2%, 8·1-8·4]), HbA1c changed by -3·2 mmol/mol (-5·0 to -1·4 [-0·3%, -0·5 to -0·1]) with exenatide and -2·1 mmol/mol (-3·7 to -0·6 [-0·2%, -0·3 to -0·1]) with placebo after 26 weeks (estimated treatment difference of -1·1 mmol/mol (-3·4 to 1·2 [-0·1%, -0·3 to 0·1]; p=0·36). Exenatide increased the number of self-reported gastrointestinal adverse events (primarily nausea [48 events among 37 patients with exenatide, nine with placebo among 9 patients]). Two serious adverse events occurred in the exenatide group, and six occurred in the placebo group (none were considered to be related to the study drug). INTERPRETATION: Short-acting exenatide does not seem to have a future as a standard add-on treatment to insulin therapy in type 1 diabetes. FUNDING: AstraZeneca.

Investigating Intestinal Glucagon After Roux-en-Y Gastric Bypass Surgery.

CONTEXT: After Roux-en-Y gastric bypass (RYGB) surgery, postprandial plasma glucagon concentrations have been reported to increase. This occurs despite concomitant improved glucose tolerance and increased circulating plasma concentrations of insulin and the glucagon-inhibiting hormone glucagon-like peptide 1 (GLP-1). OBJECTIVE: To investigate whether RYGB-induced hyperglucagonemia may be derived from the gut. DESIGN AND SETTING: Substudy of a prospective cross-sectional study at a university hospital in Copenhagen, Denmark. PARTICIPANTS: Morbidly obese individuals undergoing RYGB (n = 8) with or without type 2 diabetes. INTERVENTIONS: Three months before and after RYGB, participants underwent upper enteroscopy with retrieval of gastrointestinal mucosal biopsy specimens. Mixed-meal tests were performed 1 week and 3 months before and after RYGB. MAIN OUTCOME MEASURES: The 29-amino acid glucagon concentrations in plasma and in mucosal gastrointestinal biopsy specimens were assessed using mass spectrometry-validated immunoassays, and a new monoclonal antibody reacting with immunoreactive glucagon was used for immunohistochemistry. RESULTS: Postprandial plasma concentrations of glucagon after RYGB were increased. Expression of the glucagon gene in the small intestine increased after surgery. Glucagon was identified in the small-intestine biopsy specimens obtained after, but not before, RYGB. Immunohistochemically, mucosal biopsy specimens from the small intestine harbored cells costained for GLP-1 and immunoreactive glucagon. CONCLUSION: Increased concentrations of glucagon were observed in small-intestine biopsy specimens and postprandially in plasma after RYGB. The small intestine harbored cells immunohistochemically costaining for GLP-1 and glucagon-like immunoreactivity after RYGB. Glucagon derived from small-intestine enteroendocrine l cells may contribute to postprandial plasma concentrations of glucagon after RYGB.

Rectal Insulin Instillation Inhibits Inflammation and Tumor Development in Chemically Induced Colitis.

BACKGROUND AND AIMS: Epithelial expression of the insulin receptor in the colon has previously been reported to correlate with extent of colonic inflammation. However, the impact of insulin signalling in the intestinal mucosa is still unknown. Here, we investigated the effects of inactivating the epithelial insulin receptor in the intestinal tract, in an experimental model of inflammation-induced colorectal cancer. METHODS: The mice were generated by utilizing the intestinal- and epithelial-specific villin promoter and the Cre-Lox technology. All mice included in the cohorts were generated by crossing [vil-Cre-INSR+/-] × [INSRfl/fl] to obtain [vil-Cre-INSR-/-], and their floxed littermates [INSRfl/fl] served as the control group. For the intervention study, phosphate-buffered saline with or without insulin was instilled rectally in anaesthetized wild-type mice with chemically induced colitis. RESULTS: We found higher endoscopic colitis scores together with potentiated colonic tumorigenesis in the knockout mice. Furthermore, we showed that topically administered insulin in inflamed colons of wild-type mice reduced inflammation-induced weight loss and improved remission in a dose-dependent manner. Mice receiving rectal insulin enemas exhibited lower colitis endoscopic scores and reduced cyclooxygenase 2 mRNA expression, and developed significantly fewer and smaller tumours compared with the control group receiving phosphate-buffered saline only. CONCLUSIONS: Rectal insulin therapy could potentially be a novel treatment, targeting the epithelial layer to enhance mucosal healing in ulcerated areas. Our findings open up new possibilities for combination treatments to synergize with the existing anti-inflammatory therapies.

Association Between Spousal Suicide and Mental, Physical, and Social Health Outcomes: A Longitudinal and Nationwide Register-Based Study.

Importance: Bereavement after spousal suicide has been linked to mental disorders; however, a comprehensive assessment of the effect of spousal suicide is needed. Objective: To determine whether bereavement after spousal suicide was linked to an excessive risk of mental, physical, and social health outcomes when compared with the general population and spouses bereaved by other manners. Design, Setting, and Participants: This nationwide, register-based cohort study conducted in Denmark of 6.7 million individuals aged 18 years and older from 1980 to 2014 covered more than 136 million person-years and compared people bereaved by spousal suicide with the general population and people bereaved by other manners of death. Incidence rate ratios were calculated using Poisson regressions while adjusting for sociodemographic characteristics and the presence of mental and physical disorders. Main Outcomes and Measures: Mental disorders (any disorder, mood, posttraumatic stress disorder, anxiety, alcohol use disorders, drug use disorders, and self-harm); physical disorders (cancers, diabetes, sleep disorder, cardiovascular diseases, chronic lower respiratory tract diseases, liver cirrhosis, and spinal disc herniation); causes of mortality (all-cause, natural, unintentional, suicide, and homicide); social health outcomes; and health care use. Results: The total study population included 3 491 939 men, 4814 of whom were bereaved by spousal suicide, and 3 514 959 women, 10 793 of whom were bereaved by spousal suicide. Spouses bereaved by a partner's suicide had higher risks of developing mental disorders within 5 years of the loss (men: incidence rate ratio, 1.8; 95% CI, 1.6-2.0; women: incidence rate ratio, 1.7; 95% CI, 1.6-1.8) than the general population. Elevated risks for developing physical disorders, such as cirrhosis and sleep disorders, were also noted as well as the use of more municipal support, sick leave benefits, and disability pension funds than the general population. Compared with spouses bereaved by other manners of death, those bereaved by suicide had higher risks for developing mental disorders (men: incidence rate ratio, 1.7; 95% CI, 1.5-1.9; women: incidence rate ratio, 2.0; 95% CI, 1.9-2.2), suicidal behaviors, mortality, and municipal support. Additionally, a higher level of mental health care use was noted. Conclusions and Relevance: Exposure to suicide is stressful and affects the bereaved spouse on a broad range of outcomes. The excess risks of mental, physical, and social health outcomes highlight a need for more support directed toward spouses bereaved by suicide.

Predictive risk factors for persistent postherniotomy pain.

BACKGROUND: Persistent postherniotomy pain (PPP) affects everyday activities in 5-10% of patients. Identification of predisposing factors may help to identify the risk groups and guide anesthetic or surgical procedures in reducing risk for PPP. METHODS: A prospective study was conducted in 464 patients undergoing open or laparoscopic transabdominal preperitoneal elective groin hernia repair. Primary outcome was identification of risk factors for substantial pain-related functional impairment at 6 months postoperatively assessed by the validated Activity Assessment Scale (AAS). Data on potential risk factors for PPP were collected preoperatively (pain from the groin hernia, preoperative AAS score, pain from other body regions, and psychometric assessment). Pain scores were collected on days 7 and 30 postoperatively. Sensory functions including pain response to tonic heat stimulation were assessed by quantitative sensory testing preoperatively and 6 months postoperatively to assess nerve damage. RESULTS: Four hundred sixty-four patients were included, whereof 442 were examined at 6 months (95.3% follow-up). Fifty-five patients (12.4%) had "moderate/severe" PPP at 6 months. Logistic regression analysis identified four risk factors for PPP: preoperative AAS score, preoperative pain to tonic heat stimulation, 30-day postoperative pain intensity, and sensory dysfunction in the groin at 6 months (nerve damage) (all P < 0.03). A risk prediction model of only preoperative factors and choice of surgical technique revealed increased preoperative AAS score, increased preoperative pain to heat stimulation, and open surgery to increase the risk for PPP (all P < 0.02). CONCLUSION: PPP is related to both patient and surgical factors. Patients with a high preoperative AAS score and high pain response to a standardized heat stimulus may preferably be treated using an operative technique with lowest risk for nerve damage.