Search

Thomas Leth Jensen,1 Andreas Brønden,1 Kristian Karstoft,1,2 David Peick Sonne,1,2 Mikkel Bring Christensen1– 3 1Department of Clinical Pharmacology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, DK-2400, Denmark; 2Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK-2200, Denmark; 3Center for Translational Research, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, DK-2400, DenmarkCorrespondence: Mikkel Bring Christensen, Email Mikkel.bring.christensen@regionh.dkAbstract: Obesity is becoming more frequent and has several negative health impacts. Recent advances in weight management strategies have primarily resided in pharmaceutical treatments, and the glucagon-like peptide-1 (GLP-1) receptor agonists have shown great potential in terms of body weight reduction in addition to improving glycemic control in patients with type 2 diabetes (T2D). Recently, the dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide has been developed. Tirzepatide has shown strong effects on glycated hemoglobin (HbA1C) levels in several clinical trials including participants with T2D (SURPASS program). In addition to its lowering effect on HbA1C, tirzepatide leads to substantial reductions in body weight, and a series of clinical trials (SURMOUNT program) have investigated the effects on body weight as the primary outcome. In these two trial programs, tirzepatide in doses of 5 mg to 15 mg administered subcutaneously once weekly resulted in body weight reduction of up to 15% in participants with T2D and up to 21% in participants without T2D, despite comparable baseline bodyweight. Across the two trial programs, adverse effects were mainly gastrointestinal (nausea, diarrhea, and vomiting) occurring with similar incidences of vomiting and lower incidences of diarrhea and nausea in trial participants with T2D compared to trials participants without T2D. Overall, discontinuation due to adverse events occurred in 3– 7% of participants with no major differences between individuals with and without T2D. The higher weight-reducing efficacy of tirzepatide in trial participants without T2D is currently unexplained and may be partly reflected in dissimilarities in frequencies of gastrointestinal adverse events. The weight reducing effects of tirzepatide hold great promise for weight management in obese patients regardless of the presence of T2D.Keywords: tirzepatide, weight loss, type 2 diabetes, GLP-1, GIP, dual agonists, safety

Morten Breinholt Søvsø,1,2 Bodil Hammer Bech,3 Helle Collatz Christensen,4 Linda Huibers,2 Erika Frischknecht Christensen,1 Morten Bondo Christensen2 1Centre for Prehospital and Emergency Research, Aalborg University and Aalborg University Hospital, Aalborg, Denmark; 2Research Unit for General Practice, Aarhus, Denmark; 3Department of Public Health, Research Unit for Epidemiology, Aarhus University, Aarhus, Denmark; 4Emergency Medical Services, Copenhagen, University of Copenhagen, Copenhagen, DenmarkCorrespondence: Morten Breinholt SøvsøCentre for Prehospital and Emergency Research, Aalborg University and Aalborg University Hospital, Søndre Skovvej 15, Aalborg 9000, DenmarkTel +45 9764 4446Email morten.soevsoe@rn.dkBackground: Out-of-hours (OOH) health care services are often divided into emergency medical services (EMS) and OOH primary care (OOH-PC). EMS and many OOH-PC use telephone triage, yet the patient still makes the initial choice of contacting a service and which service. Sociodemographic characteristics are associated with help-seeking. Yet, differences in characteristics for EMS and OOH-PC patients have not been investigated in any large-scale cohort studies. Such knowledge may contribute to organizing OOH services to match patient needs. Thus, in this study we aimed to explore which sociodemographic patient characteristics were associated with utilizing OOH health care and to explore which sociodemographic characteristics were associated with EMS or OOH-PC contact.Methods: A population-based observational cohort study of inhabitants in two regions (North Denmark Region and Capital Region of Copenhagen) with or without contact to OOH services during 2016 was conducted. Associations between sociodemographic characteristics and OOH contacts (and EMS versus OOH-PC contact) were evaluated by regression analyses.Results: We identified 619,857 patients with OOH contact. Female sex (IRR=1.16 (95% CI: 1.16– 1.17)), non-western ethnicity (IRR=1.02 (95% CI: 1.01– 1.02)), living alone (IRR=1.08 (95% CI: 1.08– 1.09)), age groups ≥ 81 years (IRR=2.00 (95% CI: 1.98– 2.02)) and 0– 18 years (IRR=1.66 (95% CI: 1.66– 1.67)) and low income (IRR=1.41 (95% CI: 1.40– 1.42)) were more likely to contact OOH health care compared to males, Danish ethnicity, citizens cohabitating, age 31– 65 years and high income. Disability pensioners more often contacted OOH care (IRR=1.79 (95% CI: 1.77– 1.81) compared to employees. Old age (≥ 81 years) (OR=3.21 (95% CI: 3.13– 3.30)), receiving cash benefits (OR=2.45 (95% CI: 2.36– 2.54)), low income (OR=1.76 (95% CI: 1.72– 1.81)) and living alone (OR=1.40 (95% CI: 1.37– 1.42)) were all associated with EMS contacts rather than OOH-PC contacts.Conclusion: Several sociodemographic factors were associated with contacting a health care service outside office hours and with contacting EMS rather than OOH-PC. Old age, low income, low education and low socioeconomic status were of greatest importance.Keywords: out-of-hours health care, delivery of health care, Denmark, telephone hotline, telephone triage

BACKGROUND: The need to optimize frequent attender (FA) care and to economize on scarce resources in primary care has given rise to calls for intervention. However, precise knowledge of the specifics of this need is scarce, as is knowledge of how best to orchestrate intervention vis-à-vis particular FA groups. The aim of the study was to analyse the need for a special FA status consultation and to analyse if such need springs from physical, mental or social factors among FAs. METHOD: Half of the 270 general practices in the County of Aarhus, Denmark, were randomly allocated to the study group (in total 132 practices; 220 general practitioners (GPs)). From these practices age- and gender-stratified samples of FAs were drawn. FAs were defined as the top 10 per cent attenders in 12 months. Questionnaires were used to elicit FA and GP attitudes to the introduction of a status consultation and to obtain GPs' evaluation of their FAs' physical, mental and social status. The special FA consultation was introduced as a reimbursed half-hour consultation where the FA and the GP could discuss the patient's current and future care status. RESULTS: Over three-quarters of the FAs would accept the offer to have the status consultation, and the GPs would recommend it for one-fourth of their FAs. The expressed need was highly associated with an expected positive effect on health (prevalence ratio (PR) for GPs: 11.7 (8.9-15.5), PR for FAs: 1.6 (1.5-1.8)) and a decrease in attendance (PR for FAs: 1.4 (1.3-1.5)). The GPs quoted physical, mental and social indications for the consultation. The FAs who had high levels of functional symptoms were most likely to accept the consultation. CONCLUSIONS: There was an expressed need for an FA status consultation, which may lead to a positive effect on health and attendance. The GPs pointed to physical, mental and social indicators for a special FA consultation. [ABSTRACT FROM AUTHOR]

Background: Motivational interviewing approaches are currently recommended in primary prevention and treatment of cardiovascular disease (CVD) in general practice in Denmark, based on an empirical and multidisciplinary body of scientific knowledge about the importance of motivation for successful lifestyle change among patients at risk of lifestyle related diseases. This study aimed to explore and describe motivational aspects related to potential lifestyle changes among patients at increased risk of CVD following preventive consultations in general practice.Methods: Individual interviews with 12 patients at increased risk of CVD within 2 weeks after the consultation. Grounded theory was used in the analysis.Results: Ambivalence related to potential lifestyle changes was the core motivational aspect in the interviews, even though the patients rarely verbalised this experience during the consultations. The patients experienced ambivalence in the form of conflicting feelings about lifestyle change. Analysis showed that these feelings interacted with their reflections in a concurrent process. Analysis generated a typology of five different ambivalence sub-types: perception, demand, information, priority and treatment ambivalence.Conclusion: Ambivalence was a common experience in relation to motivation among patients at increased risk of CVD. Five different ambivalence sub-types were found, which clinicians may use to explore and resolve ambivalence in trying to aid patients to adopt lifestyle changes. Future research is needed to explore whether motivational interviewing and other cognitive approaches can be enhanced by exploring ambivalence in more depth, to ensure that lifestyle changes are made and sustained. Further studies with a wider range of patient characteristics are required to investigate the generalisability of the results. [ABSTRACT FROM AUTHOR]

It is not completely clear which organs are responsible for glucagon elimination in humans, and disturbances in the elimination of glucagon could contribute to the hyperglucagonemia observed in chronic liver disease and chronic kidney disease (CKD). Here, we evaluated kinetics and metabolic effects of exogenous glucagon in individuals with stage 4 CKD (n = 16), individuals with Child-Pugh A-C cirrhosis (n = 16), and matched control individuals (n = 16), before, during, and after a 60-min glucagon infusion (4 ng/kg/min). Individuals with CKD exhibited a significantly lower mean metabolic clearance rate of glucagon (14.0 [95% CI 12.2;15.7] mL/kg/min) compared with both individuals with cirrhosis (19.7 [18.1;21.3] mL/kg/min, P < 0.001) and control individuals (20.4 [18.1;22.7] mL/kg/min, P < 0.001). Glucagon half-life was significantly prolonged in the CKD group (7.5 [6.9;8.2] min) compared with individuals with cirrhosis (5.7 [5.2;6.3] min, P = 0.002) and control individuals (5.7 [5.2;6.3] min, P < 0.001). No difference in the effects of exogenous glucagon on plasma glucose, amino acids, or triglycerides was observed between groups. In conclusion, CKD, but not liver cirrhosis, leads to a significant reduction in glucagon clearance, supporting the kidneys as a primary site for human glucagon elimination., (© 2024 by the American Diabetes Association.)

Background: Antibiotic prescription rates can be affected by pandemic measures such as lockdowns, social distancing, and remote consultations in general practice. Therefore, such emergency states may negatively affect antimicrobial stewardship, specifically in out-of-hours (OOH) primary care. As contact patterns changed in the COVID-19 pandemic, it would be relevant to explore the impact on antimicrobial stewardship., Aim: To study the impact of the pandemic on antibiotic prescription rates in OOH primary care, overall and per age group., Methods: This cross-sectional register-based study used routine data from OOH primary care in the Central Denmark Region. We included all patient contacts in two equivalent time periods: pre-pandemic and pandemic period. The main outcome measure was defined as the number of antibiotic prescriptions per contact (antibiotic prescription rate)., Results: The overall antibiotic prescription rate decreased during the first year of the pandemic compared to the pre-pandemic period (RR = 0.97, 95%CI: 0.96-0.98). Likewise, the rate decreased for clinic consultations (RR = 0.63, 95%CI: 0.62-0.64). However, an increase was seen for telephone consultations (RR = 1.73, 95%CI: 1.70-1.76). The decline in clinic consultations was largest for consultations involving children aged 0-10 years (RR = 0.53, 95%CI: 0.51-0.56)., Conclusion: Antibiotic prescription rates in Danish OOH primary care decreased during the first year of the COVID-19 pandemic, especially for young children. Prescription rates decreased in clinic consultations, whereas the rates increased in telephone consultations. Further research should explore if antibiotic prescription rates have returned to pre-pandemic levels, and if the introduction of video consultations has affected antibiotic prescription patterns in OOH primary care.

Objective: Developments in pharmacotherapy and management of type 2 diabetes may have shifted the balance of treatment benefits versus harms and costs over the past decades. This study aimed to describe the trends in this balance., Research Design and Methods: We followed the Danish population with type 2 diabetes between 2002 and 2020, analyzing their medication use in relation to treatment benefits (such as mortality and diabetes-related outcomes), adverse events, and medication costs. Using multivariate analyses, we adjusted for potential confounders, including age, sex, and socioeconomic status., Results: The study included 461,805 individuals. From 2002 to 2020, the median age increased from 66 to 68 years, and the mean number of comorbidities increased from 5.2 to 8.8. The overall incidence of cardiovascular, renal, and other important adverse clinical outcomes decreased. Similarly, the rate of some adverse events, such as gastric bleeding, hypoglycemia, and falls declined, whereas the incidence of electrolyte imbalances and ketoacidosis increased. The average per-patient cost was reduced by 8%, but total medication expenses increased by 148% due to an expanding population size, lowered costs of most cardiovascular medications, and increasing costs for glucose-lowering drugs., Conclusions: Advancements in type 2 diabetes management have led to reduced risk of both diabetes-related outcomes and treatment harms, while maintaining relatively stable per-patient medication expenses. Although these trends are multifactorial, they suggest more rational pharmacotherapy. Still, increased risk of certain adverse events, along with increasing costs for glucose-lowering medications, underscores the need for ongoing vigilance and risk-benefit analysis., (© 2024 by the American Diabetes Association.)

Background: Task shifting from general practitioners (GPs) to other health professionals could solve the increased workload, but an overview of the evidence is lacking for out-of-hours primary care (OOH-PC)., Objectives: To evaluate the content and quality of task shifting from GPs to other health professionals in clinic consultations and home visits in OOH-PC., Methods: Four database literature searches were performed on 13 December 2021, and updated in August 2023. We included articles that studied content (patient characteristics, reason for encounter) and/or quality (patient satisfaction, safety, efficiency) of task shifting in face-to-face contacts at OOH-PC. Two authors independently screened articles for inclusion and assessed the methodological quality of included articles using the JBI critical appraisal checklist. Data was extracted and results were synthesised in a narrative summary., Results: The search identified 1,829 articles, resulting in the final inclusion of seven articles conducted in the UK or the Netherlands. Studies compared GPs with other health professionals (mainly nurses). These other health professionals saw patients with less urgent health problems, younger patients, and patients with less complex health problems than GPs. Most studies concluded that other health professionals provided safe and vastly efficient care corresponding to the level of GPs but findings about productivity were inconclusive., Conclusion: The level of safety and efficiency of care provided by other health professionals in OOH-PC seems like that of GPs, although they mainly see patients presenting with less urgent and less complex health problems.

Objective: The lack of descriptions for education programs in studies evaluating the efficacy of continuous glucose monitoring (CGM) compared to blood glucose monitoring (BGM) for individuals with T2DM makes it difficult to compare results across trials. This study aimed to develop and evaluate a new education program for adults with insulin-treated T2DM and HbA1c ≥58 mmol/mol (7.5 %) initiating CGM., Methods: A 3-h education program was created to provide information on diabetes self-management and CGM or BGM based on international guidelines and a pre-evaluation based on user needs assessment. Questionnaires were used to post-evaluate participant-rated benefits from the program., Results: Seven individuals attended a user needs assessment of the program and 96 participated in the final education program (61.5 % men, mean age 61 (59.5;63) years, mean diabetes duration 18.2 (16.9;19.5) years, and median HbA1c 69 (63-78)mmol/mol (8.5 (7.9-9.3)%). Benefit from this program was rated good/very good by 95.5 % with no statistically significant difference between glucose monitoring groups., Conclusions: This study presents a new well-received education program for T2DM for both the CGM and BGM group., Innovation: The description of the development process and the education provided for both glucose monitoring groups may be useful for CGM initiation in clinics and trials., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

In this systematic review, we assessed the safety and possible safety events of native glucose-dependent insulinotropic polypeptide (GIP)(1-42) in human studies with administration of synthetic human GIP. We searched the PubMed database for all trials investigating synthetic human GIP(1-42) administration. A total of 67 studies were included. Study duration ranged from 30 min to 6 days. In addition to healthy individuals, the studies included individuals with impaired glucose tolerance, type 2 diabetes, type 1 diabetes, chronic pancreatitis and secondary diabetes, latent autoimmune diabetes in adults, diabetes caused by a mutation in the hepatocyte nuclear factor 1-alpha gene, end-stage renal disease, chronic renal insufficiency, critical illness, hypoparathyroidism, or cystic fibrosis-related diabetes. Of the included studies, 78% did not mention safety events, 10% of the studies reported that no safety events were observed in relation to GIP administration, and 15% of the studies reported safety events in relation to GIP administration with most frequently reported event being a moderate and transient increased heart rate. Gastrointestinal safety events, and changes in blood pressure were also reported. Plasma concentration of active GIP(1-42) increased linearly with dose independent of participant phenotype. There was no significant correlation between achieved maximal concentration of GIP(1-42) and reported safety events. Clearance rates of GIP(1-42) were similar between participant groups. In conclusion, the available data indicate that GIP(1-42) in short-term (up to 6 days) infusion studies is generally well-tolerated. The long-term safety of continuous GIP(1-42) administration is unknown., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims: To explore the feasibility and potential benefits of a peer support programme for adults with insulin-treated type 2 diabetes (T2D) starting continuous glucose monitoring (CGM)., Methods: This part of the Steno2tech study is an exploratory, single-centre, open-labelled, prospective, randomised controlled trial (RCT). A total of 60 participants were randomised 2:1 to 12 months of CGM with or without peer support. All participants received a 3-h diabetes self-management education course including a CGM part on how to use the CGM and interpret the CGM-derived data. Peer support consisted of three 3-h peer support meetings over the first 6 months of the study period with groups of three to six people. The exploratory outcomes included the acceptability and feasibility of the peer support intervention, and the between-group difference in change in several glycaemic, metabolic and participant-reported outcomes measured at baseline, 6 and 12 months., Results: The peer support intervention was found acceptable and feasible. Participants shared their experiences of using and interpreting CGM data and its association with health behaviour. While both groups had improvements in glycaemic, metabolic and participant-reported outcomes, there were no significant between-group differences., Conclusions: Although feasible, we found no measured additional benefits when adding a peer support programme after starting CGM in this exploratory RCT including adults with insulin-treated T2D. Understanding the perceived effect of and preferences for a peer support intervention from the participants' points of view, including why individuals declined to participate, would be of value for future research., (© 2024 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Introduction: Available evidence suggests that as we age, our brain and immune system undergo changes that increase our susceptibility to injury, inflammation, and neurodegeneration. Since a significant portion of the potential patients treated with a microelectrode-based implant may be older, it is important to understand the recording performance of such devices in an aged population., Methods: We studied the chronic recording performance and the foreign body response (FBR) to a clinically used microelectrode array implanted in the cortex of 18-month-old Sprague Dawley rats., Results and Discussion: To the best of our knowledge, this is the first preclinical study of its type in the older mammalian brain. Here, we show that single-unit recording performance was initially robust then gradually declined over a 12-week period, similar to what has been previously reported using younger adult rats and in clinical trials. In addition, we show that FBR biomarker distribution was similar to what has been previously described for younger adult rats implanted with multi-shank recording arrays in the motor cortex. Using a quantitative immunohistochemcal approach, we observed that the extent of astrogliosis and tissue loss near the recording zone was inversely related to recording performance. A comparison of recording performance with a younger cohort supports the notion that aging, in and of itself, is not a limiting factor for the clinical use of penetrating microelectrode recording arrays for the treatment of certain CNS disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Nolta, Christensen and Tresco.)

Objective: Type 2 diabetes often coexists with other conditions that are amenable to pharmacological treatment. We hypothesized that polypharmacy among individuals with type 2 diabetes has increased since 2000., Research Design and Methods: Using Danish national registries, we established a cohort of all Danish individuals (aged ≥18 years) with type 2 diabetes between 2000 and 2020. We analyzed their medication use and prevalence of varying degrees of polypharmacy (≥5 or ≥10 medications), stratifying by age, sex, number of chronic diseases, and socioeconomic status., Results: The cohort grew from 84,917 patients in 2000 to 307,011 in 2020, totaling 461,849 unique patients. The number of daily medications used per patient increased from (mean ± SD) 3.7 ± 2.8 (in 2000) to 5.3 ± 3.2 (in 2020). The lifetime risk of polypharmacy was substantial, with 89% (n = 409,062 of 461,849) being exposed to ≥5 medications at some point and 47% (n = 217,467of 461,849) to ≥10 medications. The increases were driven by an expanding group of medications, with analgesics, antihypertensives, proton pump inhibitors, and statins having the largest net increase. Advanced age, male sex, lower socioeconomic status, and Danish ethnicity positively correlated with polypharmacy but could not explain the overall increase in polypharmacy., Conclusions: Medication use and polypharmacy have increased among patients with type 2 diabetes. Although the implications and appropriateness of this increased medication use are uncertain, the results stress the increasing need for health care personnel to understand the potential risks associated with polypharmacy, including medication interactions, adverse effects, and over- and underprescribing., (© 2024 by the American Diabetes Association.)

Objective: To compare the 12-month effects of continuous glucose monitoring (CGM) versus blood glucose monitoring (BGM) in adults with insulin-treated type 2 diabetes., Research Design and Methods: This is a single-center, parallel, open-label, randomized controlled trial including adults with inadequately controlled, insulin-treated type 2 diabetes from the outpatient clinic at Steno Diabetes Center Copenhagen, Denmark. Inclusion criteria were ≥18 years of age, insulin-treated type 2 diabetes, and HbA1c ≥7.5% (58 mmol/mol). Participants were randomly assigned (1:1) to 12 months of either CGM or BGM. All participants received a diabetes self-management education course and were followed by their usual health care providers. Primary outcome was between-group differences in change in time in range (TIR) 3.9-10.0 mmol/L, assessed at baseline, after 6 and 12 months by blinded CGM. The prespecified secondary outcomes were differences in change in several other glycemic, metabolic, and participant-reported outcomes., Results: The 76 participants had a median baseline HbA1c of 8.3 (7.8, 9.1)% (67 [62-76] mmol/mol), and 61.8% were male. Compared with BGM, CGM usage was associated with significantly greater improvements in TIR (between-group difference 15.2%, 95% CI 4.6; 25.9), HbA1c (-0.9%, -1.4; -0.3 [-9.4 mmol/mol, -15.2; -3.5]), total daily insulin dose (-10.6 units/day, -19.9; -1.3), weight (-3.3 kg, -5.5; -1.1), and BMI (-1.1 kg/m2, -1.8; -0.3) and greater self-rated diabetes-related health, well-being, satisfaction, and health behavior., Conclusions: In adults with inadequately controlled insulin-treated type 2 diabetes, the 12-month impact of CGM was superior to BGM in improving glucose control and other crucial health parameters. The findings support the use of CGM in the insulin-treated subgroup of type 2 diabetes., (© 2024 by the American Diabetes Association.)

Background: Nonspecific discharge diagnoses after acute hospital courses represent patients discharged without an established cause of their complaints. These patients should have a low risk of adverse outcomes as serious conditions should have been ruled out. We aimed to investigate the mortality and readmissions following nonspecific discharge diagnoses compared to disease-specific diagnoses and assessed different nonspecific subgroups., Methods: Register-based cohort study including hospital courses beginning in emergency departments across 3 regions of Denmark during March 2019-February 2020. We identified nonspecific diagnoses from the R- and Z03-chapter in the ICD-10 classification and excluded injuries, among others-remaining diagnoses were considered disease-specific. Outcomes were 30-day mortality and readmission, the groups were compared by Cox regression hazard ratios (HR), unadjusted and adjusted for socioeconomics, comorbidity, administrative information and laboratory results. We stratified into short (3-<12 h) or lengthier (12-168 h) hospital courses., Results: We included 192,185 hospital courses where nonspecific discharge diagnoses accounted for 50.7% of short and 25.9% of lengthier discharges. The cumulative risk of mortality for nonspecific vs. disease-specific discharge diagnoses was 0.6% (0.6-0.7%) vs. 0.8% (0.7-0.9%) after short and 1.6% (1.5-1.7%) vs. 2.6% (2.5-2.7%) after lengthier courses with adjusted HRs of 0.97 (0.83-1.13) and 0.94 (0.85-1.05), respectively. The cumulative risk of readmission for nonspecific vs. disease-specific discharge diagnoses was 7.3% (7.1-7.5%) vs. 8.4% (8.2-8.6%) after short and 11.1% (10.8-11.5%) vs. 13.7% (13.4-13.9%) after lengthier courses with adjusted HRs of 0.94 (0.90-0.98) and 0.95 (0.91-0.99), respectively. We identified 50 clinical subgroups of nonspecific diagnoses, of which Abdominal pain (n = 12,462; 17.1%) and Chest pain (n = 9,599; 13.1%) were the most frequent. The subgroups described differences in characteristics with mean age 41.9 to 80.8 years and mean length of stay 7.1 to 59.5 h, and outcomes with < 0.2-8.1% risk of 30-day mortality and 3.5-22.6% risk of 30-day readmission., Conclusions: In unadjusted analyses, nonspecific diagnoses had a lower risk of mortality and readmission than disease-specific diagnoses but had a similar risk after adjustments. We identified 509 clinical subgroups of nonspecific diagnoses with vastly different characteristics and prognosis., (© 2024. The Author(s).)

Evidence suggests that available antiemetics are equal to intravenous fluid treatment against acute nausea of other causes than motion sickness, pregnancy, anaesthesia, chemo- or radiation therapy. Each antiemetic is associated with adverse effects, which include movement disorders, sedation, and QT prolongation. Intravenous fluid and treatment directed against underlying pathology is recommended as a first-line treatment against nausea in these patients. If an antiemetic is clinically warranted, ondansetron has the most favourable ratio between side effects and price, as argued in this review., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Background: Automated insulin delivery (AID) systems offer promise in improving glycemic outcomes for individuals with type 1 diabetes. However, data on those who struggle with suboptimal glycemic levels despite insulin pump and continuous glucose monitoring (CGM) are limited. We conducted a randomized controlled trial to assess the effects of an AID system in this population., Methods: Participants with hemoglobin A 1c (HbA 1c ) ≥ 58 mmol/mol (7.5%) were allocated 1:1 to 14 weeks of treatment with the MiniMed 780G system (AID) or continuation of usual care (UC). The primary endpoint was change in time in range (TIR: 3·9-10·0 mmol/L) from baseline to week 14. After this trial period, the UC group switched to AID treatment while the AID group continued using the system. Both groups were monitored for a total of 28 weeks., Results: Forty adults (mean ± SD: age 52 ± 11 years, HbA 1c 67 ± 7 mmol/mol [8.3% ± 0.6%], diabetes duration 29 ±13 years) were included. After 14 weeks, TIR increased by 18.7% (95% confidence interval [CI] = 14.5, 22.9%) in the AID group and remained unchanged in the UC group ( P < .0001). Hemoglobin A 1c decreased by 10.0 mmol/mol (95% CI = 7.0, 13.0 mmol/mol) (0.9% [95% CI = 0.6%, 1.2%]) in the AID group but remained unchanged in the UC group ( P < .0001). The glycemic benefits of AID treatment were reproduced after the 14-week extension phase. There were no episodes of severe hypoglycemia or diabetic ketoacidosis during the study., Conclusions: For adults with type 1 diabetes not meeting glycemic targets despite use of insulin pump and CGM, transitioning to an AID system confers considerable glycemic benefits., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MBC has received speaker honorarium from Sanofi and Novo Nordisk. KN holds shares in Novo Nordisk; has been a paid consultant for Novo Nordisk and Medtronic; has received speaker honorarium and honorarium for Advisory Board to her institution from Medtronic, Novo Nordisk, Convatec, and her institution has received research funding from Zealand Pharma, Novo Nordisk, Medtronic, and Dexcom. SS was an employee at Novo Nordisk A/S during study conduct and has received speaker fees from Novo Nordisk. KR own shares in Novo Nordisk and has received speaker’s honorarium from Medtronic. AGR and OMC have nothing to disclose.

Background: Out-of-hours primary care (OOH-PC) is challenging due to high workloads, workforce shortages, and long waiting and transportation times for patients. Use of video enables triage professionals to visually assess patients, potentially ending more contacts in a telephone triage contact instead of referring patients to more resource-demanding clinic consultations or home visits. Thus, video use may help reduce use of health care resources in OOH-PC., Objective: This study aimed to investigate video use in telephone triage contacts to OOH-PC in Denmark by studying rate of use and potential associations between video use and patient- and contact-related characteristics and between video use and triage outcomes and follow-up contacts. We hypothesized that video use could serve to reduce use of health care resources in OOH-PC., Methods: This register-based study included all telephone triage contacts to OOH-PC in 4 of the 5 Danish regions from March 15, 2020, to December 1, 2021. We linked data from the OOH-PC electronic registration systems to national registers and identified telephone triage contacts with video use (video contact) and without video use (telephone contact). Calculating crude incidence rate ratios and adjusted incidence rate ratios (aIRRs), we investigated the association between patient- and contact-related characteristics and video contacts and measured the frequency of different triage outcomes and follow-up contacts after video contact compared to telephone contact., Results: Of 2,900,566 identified telephone triage contacts to OOH-PC, 9.5% (n=275,203) were conducted as video contacts. The frequency of video contact was unevenly distributed across patient- and contact-related characteristics; it was used more often for employed young patients without comorbidities who contacted OOH-PC more than 4 hours before the opening hours of daytime general practice. Compared to telephone contacts, notably more video contacts ended with advice and self-care (aIRR 1.21, 95% CI 1.21-1.21) and no follow-up contact (aIRR 1.08, 95% CI 1.08-1.09)., Conclusions: This study supports our hypothesis that video contacts could reduce use of health care resources in OOH-PC. Video use lowered the frequency of referrals to a clinic consultation or a home visit and also lowered the frequency of follow-up contacts. However, the results could be biased due to confounding by indication, reflecting that triage GPs use video for a specific set of reasons for encounters., (© Mette Amalie Nebsbjerg, Claus Høstrup Vestergaard, Katrine Bjørnshave Bomholt, Morten Bondo Christensen, Linda Huibers. Originally published in JMIR Medical Informatics (https://medinform.jmir.org).)

Context: Hyperglucagonemia is observed in individuals with obesity and contributes to the hyperglycemia of patients with type 2 diabetes. Hyperglucagonemia may develop due to steatosis-induced hepatic glucagon resistance resulting in impaired hepatic amino acid turnover and ensuing elevations of circulating glucagonotropic amino acids., Objective: We evaluated whether glucagon resistance could be induced in healthy individuals by a hypercaloric diet intervention designed to increase hepatic fat content., Methods: We recruited 20 healthy male individuals to follow a hypercaloric diet and a sedentary lifestyle for 2 weeks. Amino acid concentrations in response to infusion of glucagon were assessed during a pancreatic clamp with somatostatin and basal insulin. The reversibility of any metabolic changes was assessed 8 weeks after the intervention. Hepatic steatosis was assessed by magnetic resonance spectroscopy., Results: The intervention led to increased hepatic fat content (382% [206%; 705%], P < .01). Glucagon infusion led to a decrease in the concentration of total amino acids on all experimental days, but the percentage change in total amino acids was reduced (-2.5% ± 0.5% vs -0.2% ± 0.7%, P = .015) and the average slope of the decline in the total amino acid concentration was less steep (-2.0 ± 1.2 vs -1.2 ± 0.3 μM/min, P = .016) after the intervention compared to baseline. The changes were normalized at follow-up., Conclusion: Our results indicate that short-term unhealthy behavior, which increases hepatic fat content, causes a reversible resistance to the effect of glucagon on amino acid concentrations in healthy individuals, which may explain the hyperglucagonemia associated with obesity and diabetes., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Type 2 diabetes (T2D) treatment has changed markedly within the last decades. We aimed to explore whether people with severe mental illness (SMI) have followed the same changes in T2D treatment as those without SMI, as multiple studies suggest that people with SMI receive suboptimal care for somatic disorders., Methods: In this registry-based annual cohort study, we explored the T2D treatment from 2001 to 2015 provided in general practices of the Greater Copenhagen area. We stratified the T2D cohorts by their pre-existing SMI status. T2D was defined based on elevated glycated hemoglobin (≥48 mmol/mol) or glucose (≥11 mmol/L) using data from the Copenhagen Primary Care Laboratory Database. Individuals with schizophrenia spectrum disorders (ICD-10 F20-29) or affective disorders (bipolar disorder or unipolar depression, ICD-10 F30-33) were identified based on hospital-acquired diagnoses made within 5 years before January 1 each year for people with prevalent T2D or 5 years before meeting our T2D definition for incident patients. For comparison, we defined a non-SMI group, including people who did not have a hospital-acquired diagnosis of schizophrenia spectrum disorders, affective disorders, or personality disorders. For each calendar year, we assembled cohorts of people with T2D with or without SMI. We used Poisson regression to calculate the rates per 100 person-years of having at least one biochemical test (glycated hemoglobin, low-density lipoprotein cholesterol, estimated glomerular filtration rate, and urine albumin-creatinine ratio), having poor control of these biochemical results, taking glucose-lowering or cardiovascular medications, or experiencing a clinical outcome, including all-cause mortality and cardiovascular mortality. Three outcomes (cardiovascular events, cardiovascular mortality, and all-cause mortality) were additionally examined and adjusted for age and sex in a post hoc analysis., Results: From 2001 to 2015, 66,914 individuals were identified as having T2D. In 2015, 1.5% of the study population had schizophrenia spectrum disorder and 1.4% had an affective disorder. The number of people who used biochemical tests or had poor biochemical risk factor control was essentially unrelated to SMI status. One exception was that fewer LDL cholesterol tests were done on people with affective disorders and schizophrenia spectrum disorders at the beginning of the study period compared to people in the non-SMI group. This difference gradually diminished and was almost nonexistent by 2011. There was also a slightly slower rise in UACR test rates in the SMI groups compared to other people with T2D during the period. Throughout the study period, all groups changed their use of medications in similar ways: more metformin, less sulfonylurea, more lipid-lowering drugs, and more ACEi/ARBs. However, people with schizophrenia disorder consistently used fewer cardiovascular medications. Cardiovascular events were more common in the affective disorder group compared to the non-SMI group from 2009 to 2015 (rate ratio 2015 : 1.36 [95% CI 1.18-1.57]). After adjustment for age and sex, all-cause mortality was significantly higher among people with a schizophrenia spectrum disorder each year from 2003 to 2015 compared to the non-SMI group (rate ratio 2015 : 1.99 [95% CI 1.26-3.12])., Conclusion: Persons with schizophrenia or affective disorders demonstrated the same treatment changes for T2D as those without SMI in general practice. The lower use of most types of cardiovascular medications among people with schizophrenia disorders indicates potential undertreatment of hypertension and dyslipidemia and remains throughout the study period. Cardiovascular events were most common among people with affective disorders, but this was not reflected in a higher proportion using cardiovascular preventive medications. This knowledge should be considered in the management of this vulnerable patient group., (© 2024 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Objective: In obesity and type 2 diabetes, hyperglucagonaemia may be caused by elevated levels of glucagonotropic amino acids due to hepatic glucagon resistance at the level of amino acid turnover. Here, we investigated the effect of exogenous glucagon on circulating amino acids in obese and non-obese individuals with and without type 2 diabetes., Design: This was a post hoc analysis in a glucagon infusion study performed in individuals with type 2 diabetes (n = 16) and in age, sex, and body mass index-matched control individuals without diabetes (n = 16). Each group comprised two subgroups of eight individuals with and without obesity, respectively., Methods: All participants received a 1-h glucagon infusion (4 ng/kg/min) in the overnight fasted state. Plasma amino acid concentrations were measured with frequent intervals., Results: Compared to the control subgroup without obesity, baseline total amino acid levels were elevated in the control subgroup with obesity and in the type 2 diabetes subgroup without obesity. In all subgroups, amino acid levels decreased by up to 20% in response to glucagon infusion, which resulted in high physiological steady-state glucagon levels (mean concentration: 74 pmol/L, 95% CI [68;79] pmol/L). Following correction for multiple testing, no intergroup differences in changes in amino acid levels reached significance., Conclusion: Obesity and type 2 diabetes status was associated with elevated fasting levels of total amino acids. The glucagon infusion decreased circulating amino acid levels similarly in all subgroups, without significant differences in the response to exogenous glucagon between individuals with and without obesity and type 2 diabetes., Significance Statement: The hormone glucagon stimulates glucose production from the liver, which may promote hyperglycaemia if glucagon levels are abnormally elevated, as is often seen in type 2 diabetes and obesity. Glucagon levels are closely linked to, and influenced by, the levels of circulating amino acids. To further investigate this link, we measured amino acid levels in individuals with and without obesity and type 2 diabetes before and during an infusion of glucagon. We found that circulating amino acid levels were higher in type 2 diabetes and obesity, and that glucagon infusion decreased amino acid levels in both individuals with and without type 2 diabetes and obesity. The study adds novel information to the link between circulating levels of glucagon and amino acids.

Background: Point-of-care testing may reduce diagnostic uncertainty in case of suspicion of bacterial infection, thereby contributing to prudent antibiotic prescribing. We aimed to study variations in the use of point-of-care tests (C-reactive protein test, rapid streptococcal antigen detection test, and urine dipstick) among general practitioners (GPs) and the potential association between point-of-care testing and antibiotic prescribing in out-of-hours general practice., Methods: We conducted a population-based observational register-based study, based on patient contacts with out-of-hours general practice in the Central Denmark Region in 2014-2017. The tendency of GPs to use point-of-care testing was calculated, and the association between the use of point-of-care testing and antibiotic prescribing was evaluated with the use of binomial regression., Results: Out-of-hours general practice conducted 794,220 clinic consultations from 2014 to 2017, of which 16.1% resulted in an antibiotic prescription. The GP variation in the use of point-of-care testing was largest for C-reactive protein tests, with an observed variation (p90/p10 ratio) of 3.0; this means that the GPs in the 90th percentile used C-reactive protein tests three times as often as the GPs in the 10th percentile. The observed variation was 2.1 for rapid streptococcal antigen detection tests and 1.9 for urine dipsticks. The GPs who tended to use more point-of-care tests prescribed significantly more antibiotics than the GPs who tended to use fewer point-of-care tests. The GPs in the upper quintile of the tendency to use C-reactive protein test prescribed 22% more antibiotics than the GPs in the lowest quintile (21% for rapid streptococcal antigen detection tests and 8% for urine dipsticks). Up through the quintiles, this effect exhibited a positive linear dose-response correlation., Conclusion: The GPs varied in use of point-of-care testing. The GPs who tended to perform more point-of-care testing prescribed more antibiotics compared with the GPs who tended to perform fewer of these tests., (© 2024. The Author(s).)

Objectives: Chylothorax is a complex condition and many different pharmacological agents have been tried as treatment. Octreotide is used off-label to treat chylothorax, but the efficacy of octreotide remains unclear. A decrease in lymph production is suggested as the mechanism. In this cross-over study, we explore the direct effect of octreotide on human lymphatic drainage., Methods: Pre-clinical: the effect of octreotide on force generation was assessed during acute and prolonged drug incubation on human lymphatic vessels mounted in a myograph. Clinical: in a double-blinded, randomized, cross-over trial including 16 healthy adults, we administered either octreotide or saline as an intravenous infusion for 2.5 h. Near-infrared fluorescence imaging was used to examine spontaneous lymphatic contractions and lymph pressure in peripheral lymphatic vessels and plethysmography was performed to assess the capillary filtration rate, capillary filtration coefficient and isovolumetric pressures of the lower leg., Results: Pre-clinical: human thoracic duct (n = 12) contraction rate was concentration-dependently stimulated by octreotide with a maximum effect at 10 and 100 nmol/l in the myograph chamber. Clinical: spontaneous lymphatic contractions and lymph pressure evaluated by near-infrared fluorescence did not differ between octreotide or placebo (P = 0.36). Plethysmography revealed similar capillary filtration coefficients (P = 0.057), but almost a doubling of the isovolumetric pressures (P = 0.005) during octreotide infusion., Conclusions: Octreotide stimulated lymphatic contractility in the pre-clinical setup but did not affect the spontaneous lymphatic contractions or lymph pressure in healthy individuals. Plethysmography revealed a doubling in the isovolumetric pressure. These results suggest that octreotide increases lymphatic drainage capacity in situations with high lymphatic afterload., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Aim: To explore the impact of type 2 diabetes (T2D), glycaemic control and use of glucose-lowering medication on clinical outcomes in hospitalized patients with COVID-19., Materials and Methods: For all patients admitted to a hospital in the Capital Region of Denmark (1 March 2020 to 1 December 2021) with confirmed COVID-19, we extracted data on mortality, admission to intensive care unit (ICU), demographics, comorbidities, medication use and laboratory tests from the electronic health record system. We compared patients with T2D to patients without diabetes using Cox proportional hazards models adjusted for available confounding variables. Outcomes were 30-day mortality and admission to an ICU. For patients with T2D, we also analysed the association of baseline haemoglobin A1c (HbA1c) levels and use of specific glucose-lowering medications with the outcomes., Results: In total, 4430 patients were analysed, 1236 with T2D and 2194 without diabetes. The overall 30-day mortality was 19% (n = 850) and 10% (n = 421) were admitted to an ICU. Crude analyses showed that patients with T2D both had increased mortality [hazard ratio (HR) 1.37; 95% CI 1.19-1.58] and increased risk of ICU admission (HR 1.28; 95% CI 1.04-1.57). When adjusted for available confounders, this discrepancy was attenuated for both mortality (adjusted HR 1.13; 95% CI 0.95-1.33) and risk of ICU admission (adjusted HR 1.01; 95% CI 0.79-1.29). Neither baseline haemoglobin A1c nor specific glucose-lowering medication use were significantly associated with the outcomes., Conclusion: Among those hospitalized for COVID-19, patients with T2D did not have a higher risk of death and ICU admission, when adjusting for confounders., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: The pharmacotherapeutic guidelines for type 2 diabetes have changed considerably during the past decades. SGLT2 inhibitors and GLP-1 receptor agonists have emerged as first-line agents by preventing cardiovascular events within a few years of treatment. In contrast, sulphonylureas and insulin have been deprioritised due to less beneficial effects and the risk of hypoglycaemia-particularly in older people who are frail. We hypothesised that medications with a high risk of hypoglycaemia were used more often in older people compared with younger people., Methods: In a nationwide cohort of people with type 2 diabetes in Denmark from 2019 to 2020, we described the use of specific glucose-lowering medications in relation to age and glycated haemoglobin A 1C (HbA 1c ) by descriptive statistics and regression models adjusted for sex, socioeconomic factors, renal function, and several comorbidities., Findings: Among 290 890 people with type 2 diabetes, glucose-lowering medication usage peaked at age 70 years. Increasing age was associated with relatively less use of metformin, GLP-1 receptor agonists, and SGLT2 inhibitors and more use of basal insulin, DDP-4 inhibitors, and sulphonylureas. When comparing 80-year-olds with 60-year-olds at similar HbA 1c levels of 6·5% (48 mmol/mol), 80-year-olds used 8% (95% CI 7-10%) fewer glucose-lowering medications, were 55% less likely to receive GLP-1 receptor agonists or SGLT2 inhibitors (relative ratio 0·45, 95% CI 0·42-0·48), and 65% more likely to receive sulphonylureas (1·65, 1·54-1·76). Among 23 032 individuals aged 80 years or older with HbA 1c levels of less than 6·5% (<48 mmol/mol), 2291 (10%) used sulphonylureas or insulin., Interpretation: In Danish people with type 2 diabetes, the likelihood of using glucose-lowering medications with a high risk of hypoglycaemia (eg, sulphonylureas and basal insulin) increased with age, whereas the likelihood of using GLP-1 receptor agonists and SGLT2 inhibitors decreased. Some people aged 80 years or older with an HbA 1c level of less than 6·5% (48 mmol/mol) were potentially overtreated with sulphonylureas or insulin. These findings emphasise the importance of frequently re-evaluating glucose-lowering treatments., Funding: None., Translation: For the Danish translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Concurrent chronic diseases and treatment hereof in patients with cancer may increase mortality. In this population-based study we examined the individual and combined impact of multimorbidity and polypharmacy on mortality, across 20 cancers and with 13-years follow-up in Denmark., Materials and Methods: This nationwide study included all Danish residents with a first primary cancer diagnosed between 1 January 2005 and 31 December 2015, and followed until the end of 2017. We defined multimorbidity as having one or more of 20 chronic conditions in addition to cancer, registered in the five years preceding diagnosis, and polypharmacy as five or more redeemed medications 2-12 months prior to cancer diagnosis. Cox regression analyses were used to estimate the effects of multimorbidity and polypharmacy, as well as the combined effect on mortality., Results: A total of 261,745 cancer patients were included. We found that patients diagnosed with breast, prostate, colon, rectal, oropharynx, bladder, uterine and cervical cancer, malignant melanoma, Non-Hodgkin lymphoma, and leukemia had higher mortality when the cancer diagnosis was accompanied by multimorbidity and polypharmacy, while in patients with cancer of the lung, esophagus, stomach, liver, pancreas, kidney, ovarian and brain & central nervous system, these factors had less impact on mortality., Conclusion: We found that multimorbidity and polypharmacy was associated with higher mortality in patients diagnosed with cancer types that typically have a favorable prognosis compared with patients without multimorbidity and polypharmacy. Multimorbidity and polypharmacy had less impact on mortality in cancers that typically have a poor prognosis.

Aims: To provide posthoc analyses of a clinical trial that reported beneficial effects of medication reviews on health-related quality of life. Specifically, to describe the medication changes with a focus on deprescribing and to explore patient- and medication-related factors that may identify patients most likely to benefit from medication reviews., Methods: Posthoc analyses of data from a pragmatic, nonblinded, randomized clinical trial investigating a medication review intervention (NCT03911934) in 408 geriatric outpatients treated with ≥9 medicines., Results: In the medication review group (n = 196), 26% of the medicines prescribed at baseline were discontinued with 82% still being discontinued after 13 months. The most common reason for discontinuation was lack of indication (72% of discontinuations). The medicines most often discontinued in the medication review group compared with usual care included: metoclopramide (11/15 = 73% discontinued vs. 1/12 = 8% in usual care), acetylsalicylic acid (20/48 = 42% vs. 2/47 = 4%), simvastatin (18/48 = 38% vs. 2/58 = 3%), zopiclone (23/59 = 39% vs. 4/54 = 7%), quinine (9/14 = 64% vs. 6/16 = 38%), citalopram (4/18 = 22% vs. 0/20 = 0%) and tramadol (18/37 = 49% vs. 8/30 = 27%). Factors associated with number of deprescribed medicines included: number of prescribed medicines, Drug Burden Index, patient motivation for medicine changes, and prescriptions of metoclopramide, iron preparations, antidepressants other than selective serotonin reuptake inhibitors, nonsteroidal anti-inflammatory drugs, or drugs for urinary incontinence., Conclusion: Physician-led medication reviews resulted in persistent deprescribing of medicines in older polypharmacy patients treated with ≥9 medicines. Motivation for having their medicine changed, treatment with more medicines, and a higher burden of sedative and anticholinergic medicines characterized the patients most likely to benefit from physician-led medication reviews., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Introduction: Certain clinical events reduce life expectancy and necessitate a reassessment of patient treatment., Objective: To describe medication changes in relation to a cancer diagnosis and the end of life and to highlight challenges and limitations with such descriptions., Methods: From a cohort with all Danish patients with type 2 diabetes, we matched patients with incident cancer during 2000-2021 (n = 41,745) with patients without cancer (n = 166,994) using propensity scores. We described their medication usage from cancer diagnosis until death., Results: The 1- and 5-year mortality were 51% and 86%, respectively, in the cancer group, and 13% and 59% in the non-cancer group. In relation to cancer diagnosis and death, the use of symptomatic medications (e.g., opioids, benzodiazepines) increased (10-60 incident medications per 100 patient-months), and the use of preventive medications (e.g., antihypertensives, statins) decreased (5-30% fewer users). The changes in relation to the diagnosis were driven by patients with short observed lengths of survival (< 2 years). In contrast, changes occurring within a year before death were less dependent on survival strata, and > 60% used preventive medications in their last months., Conclusions: Medication changes in relation to a cancer diagnosis were frequent and correlated to the length of survival. The results showcase the challenges and limited clinical utility of anchoring analyses on events or death. While the former diluted the results by averaging changes across patients with vastly different clinical courses, the latter leveraged information unavailable to the treating clinicians. While medication changes were common near death, preventive medications were often used until death., (© 2023. The Author(s).)

Medication review is a pillar in the new recommendations from the Danish Health Authorities regarding patients with multimorbidity and polypharmacy. This review finds that general practitioners should be primary in coordinating medication. Medication reviews can be conducted differently with various co-interventions to try to improve cross-sectoral collaboration. It seems imperative that the interventions involve improved communication for optimal sharing and implementation of changes to the medication with primary care in a key role., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Objectives: This study examined the effects of a combination corticosteroid plus long-acting beta 2 -adrenergic agonist inhaler (IC) on rabbit phonation., Methods: White New Zealand male rabbits were assigned randomly to experimental and control groups (n = 11 per group). The experimental group received twice-daily doses of Advair HFA™ (fluticasone propionate 45 mcg and salmeterol 21 mcg) via a veterinary facemask with 1-way valve and spacer; the control group received aerosolized saline. After 8 weeks, animals were euthanized, larynges excised, frozen, and subsequently thawed and mounted on a standard bench apparatus. Phonation was elicited during 15 successive trials, and phonation threshold pressure (PTP; cmH 2 O) and flow (PTF; L/min) were quantified., Results: Repeated measures analysis of variance indicated significant differences between the experimental and control groups (p < 0.05). Mean PTP and PTF values were higher (worse) for rabbits that received Advair HFA™., Conclusion: Following 8-week exposure to ICs, rabbit larynges required greater air pressure and flow to initiate phonation. Because even modest phonation onset differences can have a meaningful clinical impact on voice function, these findings suggest that LABA ICs may put patients at risk for voice disorders. Furthermore, these voice disorders may occur within a relatively short timeframe. The results from this study have important clinical implications for voice care in those who use ICs., Level of Evidence: NA Laryngoscope, 133:2680-2686, 2023., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

Testosterone undecanoate injections (TU), an oil-based depot, is a universal hormonal-based treatment which has been associated with pulmonary oil microembolism (POME). However, the rate of POME during routine intramuscular (IM) TU injection is unknown. Here, we conduct a peer-reviewed literature review investigating POME incidents in the setting of TU injections. A total of 48 articles were selected in the literature review, which included 29 studies that used TU and reported its effects. Relatively few POME cases were reported across multiple published studies, including those that focused particularly on the occurrence rate of POME while administrating IM TU. Of the 29 individual studies, which included 7 978 patients, eight studies reported a total of 88 incidence of POME cases or cough. This included episodes of cough that were not originally declared as POME. One post market review reported 223 cases per 3,107,652 injections. When POME did occur, almost all cases resolved spontaneously within 60 min without intervention. Overall, POME was observed to be rare., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Aims: The aim of our meta-analyses was to compare the effects of glucose-lowering drugs on mortality, cardiovascular and renal endpoints for a range of type 2 diabetes (T2D) subgroups defined by their specific cardiovascular risk profile., Methods: Meta-analyses comparing drugs within the classes of GLP-1RAs and SGLT-2 inhibitors were performed and compared to sulphonylureas and DPP-4 inhibitors with available cardiovascular outcome trials. The comparison between the different classes of glucose-lowering drugs included analyses of T2D populations with low risk and high risk for cardiovascular disease including populations with established cardiovascular disease and/or kidney disease. Outcomes included mortality, major cardiovascular adverse events (MACE), hospitalisation for heart failure (HHF) and a composite renal endpoint as applied in the underlying clinical trials., Results: SGLT-2 inhibitors and GLP-1RAs showed beneficial effects on mortality and MACE compared to the classes of DPP-4 inhibitors and sulphonylureas. SGLT-2 inhibitors were shown to be the most effective treatment in terms of HHF and kidney disease. Metformin was used as background therapy for the vast majority of participants in all included studies. Overall, the absolute effects of SGLT-2 inhibitors and GLP-1RAs on these important outcomes were evident for patients with established or at high risk for cardiovascular disease but limited for the low-risk subgroup., Conclusions: The findings from our analyses substantiate the relevance of treatment with SGLT-2 inhibitors or GLP-1RAs as an add-on to metformin in patients with T2D and a high risk for cardiovascular disease, and furthermore, support the recommendation for SGLT-2 inhibitor treatment in patients with T2D and heart failure or established kidney disease., (© 2023 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Aim: To assess the effectiveness of an automated insulin delivery (AID) system around exercise in adults with type 1 diabetes (T1D). Methods: This was a three-period, randomized, crossover trial involving 10 adults with T1D (hemoglobin A1C; HbA 1c : 8.3% ± 0.6% [67 ± 6 mmol/mol]) using an AID system (MiniMed 780G; Medtronic USA). Participants performed 45 min of moderate intensity continuous exercise 90 min after consuming a carbohydrate-based meal using three strategies: (1) a 100% dose of bolus insulin with exercise announcement immediately at exercise onset "spontaneous exercise" (SE) or a 25% reduced dose of bolus insulin with exercise announcement either (2) 90 min (AE90) or (3) 45 min (AE45) before exercise. Venous-derived plasma glucose (PG) taken in 5 and 15 min intervals over a 3 h collection period was stratified into the percentage of time spent below (TBR [<3.9 mmol/L]), time in range (TIR [3.9-10 mmol/L]), and time above range (TAR [ > 10 mmol/L]). In instances of hypoglycemia, PG data were carried forward for the remainder of the visit. Results: Overall, TBR was greatest during SE (SE: 22.9 ± 22.2, AE90: 1.1 ± 1.9, AE45: 7.8% ± 10.3%, P  = 0.029). Hypoglycemia during exercise occurred in four participants in SE but one in both AE90 and AE45 ( ꭓ 2 [2] = 3.600, P  = 0.165). In the 1 h postexercise period, AE90 was associated with higher TIR (SE: 43.8 ± 49.6, AE90: 97.9 ± 5.9, AE45: 66.7% ± 34.5%, P  = 0.033), lower TBR (SE: 56.3 ± 49.6, AE90: 2.1 ± 5.9, AE45: 29.2% ± 36.5%, P  = 0.041) with the greatest source of discrepancy observed relative to SE. Conclusion: In adults using an AID system and undertaking postprandial exercise, a strategy involving both bolus insulin dose reduction and exercise announcement 90 min before commencing the activity may be most effective in minimizing dysglycemia. The study was registered as a clinical trial (Clinical Trials Register; NCT05134025).

It has been argued that persons with severe mental illness (SMI) receive poorer treatment for somatic comorbidities. This study assesses the treatment rates of glucose-lowering and cardiovascular medications among persons with incident type 2 diabetes (T2D) and SMI compared to persons with T2D without SMI. We identified persons ≥30 years old with incident diabetes (HbA1c ≥ 48 mmol/mol and/or glucose ≥ 11.0 mmol/L) from 2001 through 2015 in the Copenhagen Primary Care Laboratory (CopLab) Database. The SMI group included persons with psychotic, affective, or personality disorders within five years preceding the T2D diagnosis. Using a Poisson regression model, we calculated the adjusted rate ratios (aRR) for the redemption of various glucose-lowering and cardiovascular medications up to ten years after T2D diagnosis. We identified 1,316 persons with T2D and SMI and 41,538 persons with T2D but no SMI. Despite similar glycemic control at diagnosis, persons with SMI redeemed a glucose-lowering medication more often than persons without SMI in the period 0.5-2 years after the T2D diagnosis; for example, the aRR was 1.05 (95% CI 1.00-1.11) in the period 1.5-2 years after the T2D diagnosis. This difference was mainly driven by metformin. In contrast, persons with SMI were less often treated with cardiovascular medications during the first 3 years after T2D diagnosis, e.g., in the period 1.5-2 years after T2D diagnosis, the aRR was 0.96 (95% CI 0.92-0.99). For people with SMI in addition to T2D, metformin is more likely to be used in the initial years after T2D diagnosis, while our results suggest potential room for improvement regarding the use of cardiovascular medications., Competing Interests: ‘I have read the journal’s policy and the authors of this manuscript have the following competing interests: CB has been employed as part of her specialization in Clinical Pharmacology in Novo Nordisk in a 1-year position that ended in 2018. FP has served as a consultant, on advisory boards or as educator for AstraZeneca, Novo Nordisk, Boehringer Ingelheim, Sanofi, Mundipharma, MSD, Novartis, Amgen and has received research grants to institution from Novo Nordisk, Boehringer Ingelheim, Amgen and AstraZeneca. This does not alter our adherence to PLOS ONE policies on sharing data and materials”., (Copyright: © 2023 Bakkedal et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

A few α-glucan debranching enzymes (DBEs) of the large glycoside hydrolase family 13 (GH13), also known as the α-amylase family, have been shown to catalyze transglycosylation as well as hydrolysis. However, little is known about their acceptor and donor preferences. Here, a DBE from barley, limit dextrinase ( Hv LD), is used as a case study. Its transglycosylation activity is studied using two approaches; (i) natural substrates as donors and different p -nitrophenyl (pNP) sugars as well as different small glycosides as acceptors, and (ii) α-maltosyl and α-maltotriosyl fluorides as donors with linear maltooligosaccharides, cyclodextrins, and GH inhibitors as acceptors. Hv LD showed a clear preference for pNP maltoside both as acceptor/donor and acceptor with the natural substrate pullulan or a pullulan fragment as donor. Maltose was the best acceptor with α-maltosyl fluoride as donor. The findings highlight the importance of the subsite +2 of Hv LD for activity and selectivity when maltooligosaccharides function as acceptors. However, remarkably, Hv LD is not very selective when it comes to aglycone moiety; different aromatic ring-containing molecules besides pNP could function as acceptors. The transglycosylation activity of Hv LD can provide glycoconjugate compounds with novel glycosylation patterns from natural donors such as pullulan, although the reaction would benefit from optimization.

In an in-patient switch study, 10 adults with type 1 diabetes (T1D) performed 45 min of moderate-intensity exercise on 2 occasions: (1) when using their usual insulin pump (UP) and (2) after transitioning to automated insulin delivery (AID) treatment (MiniMed™ 780G). Consensus glucose management guidelines for performing exercise were applied. Plasma glucose concentrations measured over a 3-h monitoring period were stratified into time below range (TBR, <3.9 mmol/L), time in range (TIR, 3.9-10.0 mmol/L), and time above range (TAR, >10.0 mmol/L). Overall, TBR (UP: 11 ± 21 vs. AID: 3% ± 10%, P  = 0.413), TIR (UP: 53 ± 27 vs. AID: 66% ± 39%, P  = 0.320), and TAR (UP: 37 ± 34 vs. AID: 31% ± 41%, P  = 0.604) were similar between arms. A proportionately low number of people experienced exercise-induced hypoglycemia (UP: n  = 2 vs. AID: n  = 1, P  = 1.00). In conclusion, switching to AID therapy did not alter patterns of glycemia around sustained moderate-intensity exercise in adults with T1D. Clinical Trial Registration number: NCT05133765.

Aims: Medication reviews can be used to promote appropriate pharmacotherapy and negate the harmful consequences of polypharmacy. This study aimed to evaluate the effect of physician-led medication reviews and increased cross-sectoral communication as a supplement to standard care in a type 2 diabetes outpatient clinic., Methods: This pragmatic randomised clinical trial enrolled patients with type 2 diabetes treated with at least 12 medications. The subjects were randomised to either standard care (standard care consultation at the outpatient clinic) or standard care plus a medication review consultation and increased cross-sectoral communication. The primary outcome was the number of medications used after six months. Health-related quality of life was quantified using the EuroQoL 5-dimension 5-level (EQ5D-5 L) questionnaire., Results: We recruited 50 participants with a median age of 72 (IQR 67-75) years. The mean number of medications per patient changed from 17.9 to 14.3 in the intervention group and 17.6 to 17.2 in the control group (rate ratio 0.81). The reasons for discontinuations were medication no longer indicated (60%), safety issues (20%), efficacy issues (15%) or patient preferences (5%). There was a significant difference in the change in health-related quality of life (EQ5D-5 L index score) in favour of the intervention (0.111, 95% CI 0.001 to 0.221)., Conclusions: Physician-led medication reviews and increased cross-sectoral communication in patients with type 2 diabetes treated with at least 12 medications reduced the number of medications used and improved health-related quality of life. Implementing and further investigating similar interventions as standard care seems reasonable., (© 2023 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Objectives: We aim to explore undertriage and overtriage in a high-risk patient population and explore patient characteristics and call characteristics associated with undertriage and overtriage in both randomly selected and in high-risk telephone calls to out-of-hours primary care (OOH-PC)., Design: Natural quasi-experimental cross-sectional study., Setting: Two Danish OOH-PC services using different telephone triage models: a general practitioner cooperative with GP-led triage and the medical helpline 1813 with computerised decision support system-guided nurse-led triage., Participants: We included audio-recorded telephone triage calls from 2016: 806 random calls and 405 high-risk calls (defined as patients ≥30 years calling with abdominal pain)., Main Outcome Measures: Twenty-four experienced physicians used a validated assessment tool to assess the accuracy of triage. We calculated the relative risk (RR) for clinically relevant undertriage and overtriage for a range of patient characteristics and call characteristics., Results: We included 806 randomly selected calls (44 clinically relevant undertriaged and 54 clinically relevant overtriaged) and 405 high-risk calls (32 undertriaged and 24 overtriaged). In high-risk calls, nurse-led triage was associated with significantly less undertriage (RR: 0.47, 95% CI 0.23 to 0.97) and more overtriage (RR: 3.93, 95% CI 1.50 to 10.33) compared with GP-led triage. In high-risk calls, the risk of undertriage was significantly higher for calls during nighttime (RR: 2.1, 95% CI 1.05 to 4.07). Undertriage tended to be more likely for calls concerning patients ≥60 years compared with 30-59 years (11.3% vs 6.3%) in high-risk calls. However, this result was not significant., Conclusion: Nurse-led triage was associated with less undertriage and more overtriage compared with GP-led triage in high-risk calls. This study may suggest that to minimise undertriage, the triage professionals should pay extra attention when a call occurs during nighttime or concerns elderly. However, this needs confirmation in future studies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Here, we present a protocol for a randomized, double-blind, placebo-controlled, crossover trial to evaluate the effects of a continuous intravenous infusion of a native liver-derived hormone, liver-expressed antimicrobial peptide 2 (LEAP2), on postprandial glucose metabolism, appetite and satiety sensations, and ad libitum food intake in humans. We describe the preparation of the exogenous hormone administration and participants. We then detail the liquid mixed meal, ad libitum meal test, and blood sampling procedures for assessing postprandial glucose metabolism and food intake. For complete details on the use and execution of this protocol, please refer to Hagemann et al. (2022). 1 ., Competing Interests: Declaration of interests F.K.K. has served on scientific advisory panels and/or been part of speaker’s bureaus for, served as a consultant to, and/or received research support from Amgen, AstraZeneca, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, Gubra, MedImmune, MSD/Merck, Mundipharma, Norgine, Novo Nordisk, Sanofi, ShouTi, Zealand Pharma, and Zucara. L.S.G. has been in speaker’s bureau for Eli Lilly., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: To profile acute glycaemic dynamics during graded exercise testing (GXT) and explore the influence of glycaemic indicators on the physiological responses to GXT in adults with type 1 diabetes using insulin pump therapy., Methods: This was a retrospective analysis of pooled data from four clinical trials with identical GXT protocols. Data were obtained from 45 adults with type 1 diabetes using insulin pumps [(30 females); haemoglobin A1c 59.5 ± 0.5 mmol/mol (7.6 ± 1.0%); age 49.7 ± 13.0 years; diabetes duration 31.2 ± 13.5 years; V̇O 2peak 29.5 ± 8.0 ml/min/kg]. Integrated cardiopulmonary variables were collected continuously via spiroergometry. Plasma glucose was obtained every 3 min during GXT as well as the point of volitional exhaustion. Data were assessed via general linear modelling techniques with age and gender adjustment. Significance was accepted at p ≤ .05., Results: Despite increasing duration and intensity, plasma glucose concentrations remained similar to rest values (8.8 ± 2.3 mmol/L) throughout exercise (p = .419) with an overall change of +0.3 ± 1.1 mmol/L. Starting glycaemia bore no influence on subsequent GXT responses. Per 1% increment in haemoglobin A1c there was an associated decrease in V̇O 2peak of 3.8 ml/min/kg (p < .001) and power peak of 0.33 W/kg (p < .001) concomitant with attenuations in indices of peripheral oxygen extraction [(O 2 pulse) -1.2 ml/beat, p = .023]., Conclusion: In adults with long-standing type 1 diabetes using insulin pump therapy, circulating glucose remains stable during a graded incremental cycle test to volitional exhaustion. Glycaemic indicators are inversely associated with aerobic rate, oxygen economy and mechanical output across the exercise intensity spectrum. An appreciation of these nexuses may help guide appropriate decision making for optimal exercise management strategies., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

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., Competing Interests: Competing interests: LSG and MBC are minority shareholders of Antag Therapeutics. TV has served on scientific advisory panels, been part of speaker's bureaus for, served as a consultant to and/or received research support from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, GSK, MSD/Merck, Novo Nordisk, Sanofi and Sun Pharmaceuticals. FKK has served on scientific advisory panels, been part of speaker's bureaus for, served as a consultant to and/or received research support from Amgen, AstraZeneca, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, Gubra, MedImmune, MSD/Merck, Norgine, Novo Nordisk, Sanofi, ShouTi, SNIPR Biome, Zealand Pharma and Zucara; and is a minority shareholder of Antag Therapeutics. Other authors declare that there is no duality of interest associated with their contribution to this manuscript., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Being a general practitioner for residents in many care homes may challenge communication with residents, relatives, and care home staff, and potentially lead to lower quality of care. Several countries have therefore introduced different solutions to reduce the number of general practitioners at each care home. In 2017, the designated general practitioner model was introduced at many Danish care homes. This study aimed to evaluate experiences from the interprofessional team-based collaboration between designated general practitioners and care home staff with regular contact with the designated general practitioners in an urban Danish setting., Methods: A qualitative design was applied using semi-structured interviews. Eight interviews (three group interviews and five individual interviews) were conducted with four designated general practitioners and seven care home staff members at four care homes in an urban setting of Central Denmark Region, Denmark. The interviews were transcribed verbatim, and data were analysed using content analysis with inspiration from the theory of relational coordination. The study followed the guidelines addressed in the COREQ (Consolidated Criteria for Reporting Qualitative Research) framework., Results: The initiation of the designated general practitioner model was experienced to contribute to more clear, precise, and timely communication between care homes and the general practitioner. An improved mutual acknowledgement of roles and competencies was experienced between designated general practitioners, care home nurses, and sometimes also social and health care assistants. The more frequent visits by the general practitioners at the care homes, as a result of the designated general practitioner model, resulted in more face-to-face communication between care home staff and designated general practitioners. Professional differences in the interpretation of the patient's needs were still present, which at times caused a frustrating compromise of own professional competencies. An important reason for the overall perception of improved collaboration was attributed to the more frequent dialogue in which the care homes staff and the designated general practitioners exchanged knowledge that could be applied in future patient encounters., Conclusion: The designated general practitioner model implied an improved collaboration between general practitioners and care homes staff. Clear, precise, and timely communication between care homes and the general practitioners, as well as mutual trust and acknowledgement was experienced to be essential for the collaboration. An important reason for the overall perception of an improved collaboration was attributed to the more frequent dialogue (more frequent general practitioner visits at the care homes) in which the care homes staff and the designated general practitioners exchange knowledge which again could be applied in future patient encounters., (© 2023. The Author(s).)

Objectives: To map the randomized trial evidence describing the feasibility of discontinuing active medications with potential adverse effects in older patients., Design: Scoping review with systematic search of PubMed, Embase, and Cochrane Library., Setting and Participants: Randomized trials investigating discontinuation of a single medicine or medicine class in patients with mean age ≥65 years., Methods: We extracted trial characteristics including study design and assessed bias. As proxies for the "feasibility of discontinuation," we extracted the "dropout rate" and "disease recurrence rate.", Results: We identified 40 trials investigating discontinuation of symptomatic (n = 26), preventive (n = 6), or both preventive and symptomatic medicines (n = 8) against psychiatric (n = 10), neurologic (n = 9), musculoskeletal (n = 8), cardiovascular (n = 5), respiratory (n = 4), and urologic diseases (n = 4). Five discontinuation designs were used, 75% (30/40) of trials were placebo-controlled, and 48% (19/40) of trials had bias disfavoring discontinuation. The dropout rate was similar between the discontinuation group and the continuation group in 79% of the trials (30/38), whereas disease recurrence was similar in 72% (23/32) of the trials. In 42% (13/31) of trials reporting both dropout rate and disease recurrence rate, the differences between groups were statistically insignificant and less than 10%; these trials investigated discontinuation of cholinesterase inhibitors for Alzheimer's disease in various settings (n = 3), alendronate for osteoporosis (n = 3), glucosamine for osteoarthritis, lithium as adjunct for unipolar depression, statins for cardiovascular disease in patients with limited life expectancy, droxidopa for neurogenic orthostatic hypotension, tamsulosin for lower urinary tract symptoms, sertraline for major depressive episode, and fentanyl patch for low back or osteoarthritis pain., Conclusions and Implications: We identified 40 randomized trials using a variety of designs investigating discontinuation of both symptomatic and preventive medicines in older patients. Discontinuation of medicines seems feasible for most of the investigated medicines. This scoping review can guide clinical practice and future trials on deprescribing., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The COVID-19 pandemic caused by the virus SARS-CoV has spread rapidly and caused damage worldwide. Data suggest a major overrepresentation of hypertension and diabetes among patients experiencing severe courses of COVID-19 including COVID-19-related deaths. Many of these patients receive renin-angiotensin system (RAS) inhibiting therapy, and evidence suggests that treatment with angiotensin II receptor blockers (ARBs) could attenuate SARS-CoV-induced acute respiratory distress syndrome, and ACE inhibitors and ARBs have been suggested to alleviate COVID-19 pulmonary manifestations. This randomised clinical trial will address whether RAS inhibiting therapy should be continued or discontinued in hospitalised patients with COVID-19., Methods and Analysis: This trial is a 30-day randomised parallel-group non-inferiority clinical trial with an embedded mechanistic substudy. In the main trial, 215 patients treated with a RAS inhibitor will be included. The participants will be randomly assigned in a 1:1 ratio to either discontinue or continue their RAS inhibiting therapy in addition to standard care. The patients are included during hospitalisation and followed for a period of 30 days. The primary end point is number of days alive and out of hospital within 14 days after recruitment. In a mechanistic substudy, 40 patients treated with RAS inhibition, who are not in hospital and not infected with COVID-19 will be randomly assigned to discontinue or continue their RAS inhibiting therapy with the primary end point of serum ACE2 activity., Ethics and Dissemination: This trial has been approved by the Scientific-Ethical Committee of the Capital Region of Denmark (identification no. H-20026484), the Danish Medicines Agency (identification no. 2020040883) and by the Danish Data Protection Agency (P-2020-366). The results of this project will be compiled into one or more manuscripts for publication in international peer-reviewed scientific journals., Trial Registration Number: 2020-001544-26; NCT04351581., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Context: Glucose-dependent insulinotropic polypeptide (GIP) has been proposed to exert insulin-independent effects on lipid and bone metabolism., Objective: We investigated the effects of a 6-day subcutaneous GIP infusion on circulating lipids, white adipose tissue (WAT), brown adipose tissue (BAT), hepatic fat content, inflammatory markers, respiratory exchange ratio (RER), and bone homeostasis in patients with type 1 diabetes., Methods: In a randomized, placebo-controlled, double-blind, crossover study, 20 men with type 1 diabetes underwent a 6-day continuous subcutaneous infusion with GIP (6 pmol/kg/min) and placebo (saline), with an interposed 7-day washout period., Results: During GIP infusion, participants (26 ± 8 years [mean ± SD]; BMI 23.8 ± 1.8 kg/m2; glycated hemoglobin A1c 51 ± 10 mmol/mol [6.8 ± 3.1%]) experienced transiently increased circulating concentrations of nonesterified fatty acid (NEFA) (P = 0.0005), decreased RER (P = 0.009), indication of increased fatty acid β-oxidation, and decreased levels of the bone resorption marker C-terminal telopeptide (P = 0.000072) compared with placebo. After 6 days of GIP infusion, hepatic fat content was increased by 12.6% (P = 0.007) and supraclavicular skin temperature, a surrogate indicator of BAT activity, was increased by 0.29 °C (P < 0.000001) compared with placebo infusion. WAT transcriptomic profile as well as circulating lipid species, proteome, markers of inflammation, and bone homeostasis were unaffected., Conclusion: Six days of subcutaneous GIP infusion in men with type 1 diabetes transiently decreased bone resorption and increased NEFA and β-oxidation. Further, hepatic fat content, and supraclavicular skin temperature were increased without affecting WAT transcriptomics, the circulating proteome, lipids, or inflammatory markers., Competing Interests: Conflict of Interest: B.H. is a board member and co-founder of Bainan Biotech. J.J.H. is a board member and co-founder of Bainan Biotech and has served on advisory boards for Novo Nordisk and Merck Sharp & Dohme. T.V. has served on scientific advisory panels or speakers’ bureaus or has served as a consultant to or received research support from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, Gilead, Merck Sharp & Dohme, Mundipharma, Novo Nordisk, Sanofi, and SunPharma. T.F.D. has received lecture fees from Boehringer Ingelheim, Novo Nordisk, and AstraZeneca and research support from AstraZeneca and Novo Nordisk. F.K.K. has served on scientific advisory panels or speaker's bureaus or has served as a consultant to or received research support from Amgen, AstraZeneca, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, Gubra, MedImmune, Merck Sharp & Dohme, Mundipharma, Norgine, Novo Nordisk, Sanofi, ShouTi, Zealand Pharma, and Zucara., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Damage to the recurrent laryngeal nerve (RLN) caused by supraphysiological compression or tension imposed by adjacent tissue structures, such as the aorta, may contribute to onset of idiopathic unilateral vocal fold paralysis (iUVP) resulting in difficulty speaking, breathing, and swallowing. We previously demonstrated in adolescent pigs that the right RLN epineurium exhibits uniform composition of adipose tissue, with larger quantities along its length within the neck region in contrast to the left RLN that shows greater collagen composition in the thoracic region and greater quantities of adipose tissue in the neck region. In contrast, the epineurium in piglets was primarily composed of collagen tissue that remained uniform along the length of the left and right RLNs. Tensile testing of the left and right RLN in piglets and pigs showed associated differences in strain by RLN side and segment by age. The goal of this study was to investigate how external hydrostatic compression of the RLN affects the nerve's connective tissue and microstructure. RLN segments were harvested from the distal (cervical/neck) regions and proximal (subclavian for the right RLN, thoracic for the left RLN) regions from eight adolescent pigs and nine piglets. RLN segments were isolated and assessed under fluid compression to test hypotheses regarding epineurium composition and response to applied forces. Second harmonic generation (SHG) imaging of epineurial collagen was conducted at 0, 40, and 80 mmHg of compression. The cartesian strain tensor, principal strain (Eps1), and principal direction of the RLN collagen fibers were determined at each pressure step. Significantly larger values of the 1st principal strain occurred in the proximal segments of the pig left RLN when compared to the same segment in piglets (p = 0.001, pig = 0.0287 [IQR = 0.0161 - 0.0428], piglet = 0.0061 [IQR = 0.0033 - 0.0156]). Additionally, the median transverse strain E yy ) for the second pressure increment was larger in the right proximal segment of pigs compared to piglets (p < 0.001, pig = 0.0122 [IQR = 0.0033 - 0.0171], piglet = 0.0013 [IQR = 0.00001 - 0.0028]). E yy values were significantly larger in the right proximal RLN versus the left proximal RLNs in pigs but not in piglets (p < 0.001). In contrast to piglets, histological analysis of pig RLN demonstrated increased axial alignment of epineurial and endoneurial collagen in response to compressive pressure. These findings support the hypothesis that the biomechanical response of the RLN to compressive pressure changed from being similar to being different between the right and left RLNs during development in the porcine model. Further investigation of these findings associated with age-related onset of idiopathic UVP may illuminate underlying etiologic mechanisms. STATEMENT OF SIGNIFICANCE: Damage to the recurrent laryngeal nerve (RLN) caused by compression imposed by the aorta may contribute to the onset of left-sided idiopathic unilateral vocal fold paralysis resulting in difficulty speaking, breathing, and swallowing. The goal of this study was to investigate how compression affects the connective tissue and microstructure of the RLN. We quantified the pressure induced deformation of the RLN using multiphoton imaging as a function of both location (proximal versus distal) and age (piglets, adolescent pigs). Our results demonstrate that the biomechanical response of the RLN to compression changes in the right versus left RLN throughout development, providing further evidence that the the left RLN is exposed to increasing dynamic loads with age., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)