Immunohistochemical analysis of tumor budding in stage II colon cancer: exploring zero budding as a prognostic marker.

Tumor budding, a biomarker traditionally evaluated using hematoxylin and eosin (H&E) staining, has gained recognition as a prognostic biomarker for stage II colon cancer. Nevertheless, while H&E staining offers valuable insights, its limitations prompt the utilization of pan-cytokeratin immunohistochemistry (IHC). Consequently, this study seeks to evaluate the prognostic significance of tumor budding using IHC in a contemporary cohort of stage II colon cancer patients, aiming to deepen our understanding of this critical facet in cancer prognosis. We conducted a retrospective, population-based cohort study including 493 patients with stage II colon cancer and evaluated tumor budding using IHC, following the H&E-based guidelines proposed by the International Tumor Budding Consensus Conference Group. Correlation between H&E-based and IHC-based tumor budding was assessed using a four-tiered scoring system that included a zero budding (Bd0) category. Survival analyses explored the prognostic significance of tumor budding assessed by IHC and H&E. As expected, IHC-based tumor budding evaluation yielded significantly higher bud counts compared to H&E (p < 0.01). Interestingly, 21 patients were identified with no tumor budding using IHC. This was associated with significantly improved recurrence-free survival (HR = 5.19, p = 0.02) and overall survival (HR = 4.47, p = 0.04) in a multivariate analysis when compared to tumors with budding. The Bd0 category demonstrated a 100% predictive value for the absence of recurrence. In conclusion, IHC-based tumor budding evaluation in stage II colon cancer provides additional prognostic information. The absence of tumor budding is associated with a favorable prognosis and may serve as a potential marker for identifying patients with no risk of recurrence.

Genome-wide association study identifies host genetic variants influencing oral microbiota diversity and metabolic health.

The microbial communities of the oral cavity are important elements of oral and systemic health. With emerging evidence highlighting the heritability of oral bacterial microbiota, this study aimed to identify host genome variants that influence oral microbial traits. Using data from 16S rRNA gene amplicon sequencing, we performed genome-wide association studies with univariate and multivariate traits of the salivary microbiota from 610 unrelated adults from the Danish ADDITION-PRO cohort. We identified six single nucleotide polymorphisms (SNPs) in human genomes that showed associations with abundance of bacterial taxa at different taxonomical tiers (P < 5 × 10-8). Notably, SNP rs17793860 surpassed our study-wide significance threshold (P < 1.19 × 10-9). Additionally, rs4530093 was linked to bacterial beta diversity (P < 5 × 10-8). Out of these seven SNPs identified, six exerted effects on metabolic traits, including glycated hemoglobin A1c, triglyceride and high-density lipoprotein cholesterol levels, the risk of type 2 diabetes and stroke. Our findings highlight the impact of specific host SNPs on the composition and diversity of the oral bacterial community. Importantly, our results indicate an intricate interplay between host genetics, the oral microbiota, and metabolic health. We emphasize the need for integrative approaches considering genetic, microbial, and metabolic factors.

The interplay between birth weight and obesity in determining childhood and adolescent cardiometabolic risk.

BACKGROUND: Birth weight (BW) is associated with risk of cardiometabolic disease (CMD) in adulthood, which may depend on the state of obesity, in particular if developed at a young age. We hypothesised that BW and a polygenic score (PGS) for BW were associated with cardiometabolic risk and related plasma protein levels in children and adolescents. We aimed to determine the modifying effect of childhood obesity on these associations. METHODS: We used data from The cross-sectional HOLBAEK Study with 4263 participants (median [IQR] age, 11.7 [9.2, 14.3] years; 57.1% girls and 42.9% boys; 48.6% from an obesity clinic and 51.4% from a population-based group). We gathered information on BW and gestational age, anthropometrics, cardiometabolic risk factors, calculated a PGS for BW, and measured plasma proteins using Olink Inflammation and Cardiovascular II panels. We employed multiple linear regression to examine the associations with BW as a continuous variable and performed interaction analyses to assess the effect of childhood obesity on cardiometabolic risk and plasma protein levels. FINDINGS: BW and a PGS for BW associated with cardiometabolic risk and plasma protein levels in childhood and adolescence. Childhood obesity modified the associations between BW and measures of insulin resistance, including HOMA-IR (ßadj [95% CI per SD] for obesity: -0.12 [-0.15, -0.08]; normal weight: -0.04 [-0.08, 0.00]; Pinteraction = 0.004), c-peptide (obesity: -0.11 [-0.14, -0.08]; normal weight: -0.02 [-0.06, 0.02]; Pinteraction = 5.05E-04), and SBP SDS (obesity: -0.12 [-0.16, -0.08]; normal weight: -0.06 [-0.11, -0.01]; Pinteraction = 0.0479). Childhood obesity also modified the associations between BW and plasma levels of 14 proteins (e.g., IL15RA, MCP1, and XCL1; Pinteraction < 0.05). INTERPRETATION: We identified associations between lower BW and adverse metabolic phenotypes, particularly insulin resistance, blood pressure, and altered plasma protein levels, which were more pronounced in children with obesity. Developing effective prevention and treatment strategies for this group is needed to reduce the risk of future CMD. FUNDING: Novo Nordisk Foundation (NNF15OC0016544, NNF0064142 to T.H., NNF15OC0016692 to T.H. and A.K., NNF18CC0033668 to S.E.S, NNF18SA0034956 to C.E.F., NNF20SA0067242 to DCA, NNF18CC0034900 to NNF CBMR), The Innovation Fund Denmark (0603-00484B to T.H.), The Danish Cardiovascular Academy (DCA) and the Danish Heart Foundation (HF) (PhD2021007-DCA to P.K.R, 18-R125-A8447-22088 (HF) and 21-R149-A10071-22193 (HF) to M.A.V.L., PhD2023009-HF to L.A.H), EU Horizon (668031, 847989, 825694, 964590 to A.K.), Innovative Health Initiative (101132901 for A.K.), A.P. Møller Foundation (19-L-0366 to T.H.), The Danish National Research Foundation, Steno Diabetes Center Sjælland, and The Region Zealand and Southern Denmark Health Scientific Research Foundation.

Characterization of genetic variants of GIPR reveals a contribution of ß-arrestin to metabolic phenotypes.

Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes1. Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR-GLP-1R co-agonist tirzepatide2 and AMG-133 (ref. 3) combining GIPR antagonism with GLP-1R agonism. This underlines the importance of a better understanding of the GIP system. Here we show the necessity of ß-arrestin recruitment for GIPR function, by combining in vitro pharmacological characterization of 47 GIPR variants with burden testing of clinical phenotypes and in vivo studies. Burden testing of variants with distinct ligand-binding capacity, Gs activation (cyclic adenosine monophosphate production) and ß-arrestin 2 recruitment and internalization shows that unlike variants solely impaired in Gs signalling, variants impaired in both Gs and ß-arrestin 2 recruitment contribute to lower adiposity-related traits. Endosomal Gs-mediated signalling of the variants shows a ß-arrestin dependency and genetic ablation of ß-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of ß-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system.

Robust optimization of the Gross Tumor Volume compared to conventional Planning Target Volume-based planning in photon Stereotactic Body Radiation Therapy of lung tumors.

BACKGROUND: Robust optimization has been suggested as an approach to reduce the irradiated volume in lung Stereotactic Body Radiation Therapy (SBRT). We performed a retrospective planning study to investigate the potential benefits over Planning Target Volume (PTV)-based planning. MATERIAL AND METHODS: Thirty-nine patients had additional plans using robust optimization with 5-mm isocenter shifts of the Gross Tumor Volume (GTV) created in addition to the PTV-based plan used for treatment. The optimization included the mid-position phase and the extreme breathing phases of the 4D-CT planning scan. The plans were compared for tumor coverage, isodose volumes, and doses to Organs At Risk (OAR). Additionally, we evaluated both plans with respect to observed tumor motion using the peak tumor motion seen on the planning scan and cone-beam CTs. RESULTS: Statistically significant reductions in irradiated isodose volumes and doses to OAR were achieved with robust optimization, while preserving tumor dose. The reductions were largest for the low-dose volumes and reductions up to 188 ccm was observed. The robust evaluation based on observed peak tumor motion showed comparable target doses between the two planning methods. Accumulated mean GTV-dose was increased by a median of 4.46 Gy and a non-significant increase of 100 Monitor Units (MU) was seen in the robust optimized plans. INTERPRETATION: The robust plans required more time to prepare, and while it might not be a feasible planning strategy for all lung SBRT patients, we suggest it might be useful for selected patients.

Analysis of admixed Greenlandic siblings shows that the mean genotypic values for metabolic phenotypes differ between Inuit and Europeans.

BACKGROUND: Disease prevalence and mean phenotype values differ between many populations, including Inuit and Europeans. Whether these differences are partly explained by genetic differences or solely due to differences in environmental exposures is still unknown, because estimates of the genetic contribution to these means, which we will here refer to as mean genotypic values, are easily confounded, and because studies across genetically diverse populations are lacking. METHODS: Leveraging the unique genetic properties of the small, admixed and historically isolated Greenlandic population, we estimated the differences in mean genotypic value between Inuit and European genetic ancestry using an admixed sibling design. Analyses were performed across 26 metabolic phenotypes, in 1474 admixed sibling pairs present in a cohort of 5996 Greenlanders. RESULTS: After FDR correction for multiple testing, we found significantly lower mean genotypic values in Inuit genetic ancestry compared to European genetic ancestry for body weight (effect size per percentage of Inuit genetic ancestry (se), -0.51 (0.16) kg/%), body mass index (-0.20 (0.06) kg/m2/%), fat percentage (-0.38 (0.13) %/%), waist circumference (-0.42 (0.16) cm/%), hip circumference (-0.38 (0.11) cm/%) and fasting serum insulin levels (-1.07 (0.51) pmol/l/%). The direction of the effects was consistent with the observed mean phenotype differences between Inuit and European genetic ancestry. No difference in mean genotypic value was observed for height, markers of glucose homeostasis, or circulating lipid levels. CONCLUSIONS: We show that mean genotypic values for some metabolic phenotypes differ between two human populations using a method not easily confounded by possible differences in environmental exposures. Our study illustrates the importance of performing genetic studies in diverse populations.

Missingness mechanisms and generalizability of patient reported outcome measures in colorectal cancer survivors - assessing the reasonableness of the "missing completely at random" assumption.

BACKGROUND: Patient-Reported Outcome Measures (PROM) provide important information, however, missing PROM data threaten the interpretability and generalizability of findings by introducing potential bias. This study aims to provide insight into missingness mechanisms and inform future researchers on generalizability and possible methodological solutions to overcome missing PROM data problems during data collection and statistical analyses. METHODS: We identified 10,236 colorectal cancer survivors (CRCs) above 18y, diagnosed between 2014 and 2018 through the Danish Clinical Registries. We invited a random 20% (2,097) to participate in a national survey in May 2023. We distributed reminder e-mails at day 10 and day 20, and compared Initial Responders (response day 0-9), Subsequent Responders (response day 10-28) and Non-responders (no response after 28 days) in demographic and cancer-related characteristics and PROM-scores using linear regression. RESULTS: Of the 2,097 CRCs, 1,188 responded (57%). Of these, 142 (7%) were excluded leaving 1,955 eligible CRCs. 628 (32%) were categorized as initial responders, 418 (21%) as subsequent responders, and 909 (47%) as non-responders. Differences in demographic and cancer-related characteristics between the three groups were minor and PROM-scores only marginally differed between initial and subsequent responders. CONCLUSION: In this study of long-term colorectal cancer survivors, we showed that initial responders, subsequent responders, and non-responders exhibit comparable demographic and cancer-related characteristics. Among respondents, Patient-Reported Outcome Measures were also similar, indicating generalizability. Assuming Patient-Reported Outcome Measures of subsequent responders represent answers by the non-responders (would they be available), it may be reasonable to judge the missingness mechanism as Missing Completely At Random.

Identification of patients' smoking status using an explainable AI approach: a Danish electronic health records case study.

BACKGROUND: Smoking is a critical risk factor responsible for over eight million annual deaths worldwide. It is essential to obtain information on smoking habits to advance research and implement preventive measures such as screening of high-risk individuals. In most countries, including Denmark, smoking habits are not systematically recorded and at best documented within unstructured free-text segments of electronic health records (EHRs). This would require researchers and clinicians to manually navigate through extensive amounts of unstructured data, which is one of the main reasons that smoking habits are rarely integrated into larger studies. Our aim is to develop machine learning models to classify patients' smoking status from their EHRs. METHODS: This study proposes an efficient natural language processing (NLP) pipeline capable of classifying patients' smoking status and providing explanations for the decisions. The proposed NLP pipeline comprises four distinct components, which are; (1) considering preprocessing techniques to address abbreviations, punctuation, and other textual irregularities, (2) four cutting-edge feature extraction techniques, i.e. Embedding, BERT, Word2Vec, and Count Vectorizer, employed to extract the optimal features, (3) utilization of a Stacking-based Ensemble (SE) model and a Convolutional Long Short-Term Memory Neural Network (CNN-LSTM) for the identification of smoking status, and (4) application of a local interpretable model-agnostic explanation to explain the decisions rendered by the detection models. The EHRs of 23,132 patients with suspected lung cancer were collected from the Region of Southern Denmark during the period 1/1/2009-31/12/2018. A medical professional annotated the data into 'Smoker' and 'Non-Smoker' with further classifications as 'Active-Smoker', 'Former-Smoker', and 'Never-Smoker'. Subsequently, the annotated dataset was used for the development of binary and multiclass classification models. An extensive comparison was conducted of the detection performance across various model architectures. RESULTS: The results of experimental validation confirm the consistency among the models. However, for binary classification, BERT method with CNN-LSTM architecture outperformed other models by achieving precision, recall, and F1-scores between 97% and 99% for both Never-Smokers and Active-Smokers. In multiclass classification, the Embedding technique with CNN-LSTM architecture yielded the most favorable results in class-specific evaluations, with equal performance measures of 97% for Never-Smoker and measures in the range of 86 to 89% for Active-Smoker and 91-92% for Never-Smoker. CONCLUSION: Our proposed NLP pipeline achieved a high level of classification performance. In addition, we presented the explanation of the decision made by the best performing detection model. Future work will expand the model's capabilities to analyze longer notes and a broader range of categories to maximize its utility in further research and screening applications.

Low birthweight in patients with type 2 diabetes is associated with elevated risk of cardiovascular events and mortality.

AIMS/HYPOTHESIS: Low birthweight is a risk factor for type 2 diabetes and CVD. This prospective cohort study investigated whether lower birthweight increases CVD risk after diagnosis of type 2 diabetes. METHODS: Original midwife records were evaluated for 8417 participants recently diagnosed with type 2 diabetes in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) cohort. Patients were followed for the first occurrence of a composite CVD endpoint (myocardial infarction, coronary revascularisation, peripheral arterial disease, stroke, unstable angina, heart failure or CVD death), a three-component endpoint comprising major adverse cardiovascular events (MACE), and all-cause mortality. Ten-year risks were estimated using the Aalen-Johansen estimator considering non-CVD death as a competing risk. HRs were determined by Cox regression. Models were controlled for sex, age, calendar year at birth, family history of diabetes and born-at-term status. RESULTS: A total of 1187 composite CVD endpoints, 931 MACE, and 1094 deaths occurred during a median follow-up period of 8.5 years. The 10-year standardised composite CVD risk was 19.8% in participants with a birthweight <3000 g compared with 16.9% in participants with a birthweight of 3000-3700 g, yielding a risk difference (RD) of 2.9% (95% CI 0.4, 5.4) and an adjusted HR of 1.20 (95% CI 1.03, 1.40). The 10-year MACE risk for birthweight <3000 g was similarly elevated (RD 2.4%; 95% CI 0.1, 4.7; HR 1.22; 95% CI 1.01, 1.46). The elevated CVD risk was primarily driven by stroke, peripheral arterial disease and CVD death. All-cause mortality showed no substantial difference. CONCLUSIONS/INTERPRETATION: Having a birthweight <3000 g is associated with higher CVD risk among patients with type 2 diabetes, driven primarily by risk of stroke and CVD death.

Depletion of TBC1D4 Improves the Metabolic Exercise Response by Overcoming Genetically Induced Peripheral Insulin Resistance.

The Rab-GTPase-activating protein (RabGAP) TBC1D4 (AS160) represents a key component in the regulation of glucose transport into skeletal muscle and white adipose tissue (WAT) and is therefore crucial during the development of insulin resistance and type 2 diabetes. Increased daily activity has been shown to be associated with improved postprandial hyperglycemia in allele carriers of a loss-of-function variant in the human TBC1D4 gene. Using conventional Tbc1d4-deficient mice (D4KO) fed a high-fat diet, we show that moderate endurance exercise training leads to substantially improved glucose and insulin tolerance and enhanced expression levels of markers for mitochondrial activity and browning in WAT from D4KO animals. Importantly, in vivo and ex vivo analyses of glucose uptake revealed increased glucose clearance in interscapular brown adipose tissue and WAT from trained D4KO mice. Thus, chronic exercise is able to overcome the genetically induced insulin resistance caused by Tbc1d4 depletion. Gene variants in TBC1D4 may be relevant in future precision medicine as determinants of exercise response.

Soluble programmed death ligand 1 as prognostic biomarker in non-small cell lung cancer patients receiving nivolumab, pembrolizumab or atezolizumab therapy.

Many studies have focused on the prognostic role of soluble programmed death ligand 1 (sPD-L1) in non-small cell lung cancer (NSCLC), but outcomes are ambiguous and further investigations are needed. We addressed the matter by studying sPD-L1 in baseline samples and in longitudinal samples taken prior to three subsequent cycles of anti-PD-1/anti-PD-L1 treatments. Eighty patients with NSCLC were enrolled. Median sPD-L1 level at baseline was 52 pg/mL [95% confidence interval (CI) 49-57]. In patients treated with pembrolizumab and nivolumab, the concentration of sPD-L1 remained rather stable throughout treatment. In contrast, sPD-L1 rose by 50-fold following the first cycle of atezolizumab therapy. We found the baseline level of sPD-L1 to be related to overall survival (OS) after two years of follow-up in simple Cox analysis (p = 0.006) and multiple Cox Regression, hazard ratio 1.02 (95% CI 1.00-1.03) (p = 0.033). There was no association between sPD-L1 and tissue PD-L1 expression, overall response rate, or progression free survival. In conclusion, sPD-L1 measured in baseline serum samples may be associated with OS in NSCLC patients receiving anti-PD1/anti-PD-L1 treatment. Importantly, the results signify that further research is warranted to explore the clinical utility of sPD-L1 in patients treated with anti-PD-L1.

Genetic underpinnings of fasting and oral glucose-stimulated based insulin sensitivity indices.

CONTEXT: Insulin sensitivity (IS) is an important factor in type 2 diabetes (T2D) and can be estimated by many different indices. OBJECTIVE: We aimed to compare the genetic components underlying IS indices obtained from fasting and oral glucose-stimulated plasma glucose and serum insulin levels. METHODS: We computed 21 IS indices, classified as fasting, OGTT0,120 and OGTT0,30,120 indices, using fasting and oral glucose tolerance test (OGTT) data in two cohorts. We used data from a family cohort (n=313) to estimate the heritability and the genetic and phenotypic correlations of IS indices. The population cohort, Inter99 (n=5,343), was used to test for associations between IS indices and 426 genetic variants known to be associated with T2D. RESULTS: Heritability estimates of IS indices ranged between 19% and 38%. Fasting and OGTT0,30,120 indices had high genetic (ρG) and phenotypic (ρP) pairwise correlations (ρG and ρP: 0.88 to 1) The OGTT0,120 indices displayed a wide range of pairwise correlations (ρG: 0.17-1.00 and ρP: 0.13-0.97). We identified statistically significant associations between IS indices and established T2D-associated variants. The PPARG rs11709077 was associated only with fasting indices, and PIK3R rs4976033 only with OGTT0,30,120 indices. The variants in FAM63A/MINDY1, GCK, C2CD4A/B, and FTO loci were associated only with OGTT0,120 indices. CONCLUSION: Even though the IS indices mostly share a common genetic background, notable differences emerged between OGTT0,120 indices. The fasting and OGTT based indices have distinct associations with T2D risk variants. This work provides a basis for future large-scale genetic investigations into the differences between IS indices.

Characterization of the gut bacterial and viral microbiota in latent autoimmune diabetes in adults.

Latent autoimmune diabetes in adults (LADA) is a heterogeneous disease characterized by autoantibodies against insulin producing pancreatic beta cells and initial lack of need for insulin treatment. The aim of the present study was to investigate if individuals with LADA have an altered gut microbiota relative to non-diabetic control subjects, individuals with type 1 diabetes (T1D), and individuals with type 2 diabetes (T2D). Bacterial community profiling was performed with primers targeting the variable region 4 of the 16S rRNA gene and sequenced. Amplicon sequence variants (ASVs) were generated with DADA2 and annotated to the SILVA database. The gut virome was sequenced, using a viral particle enrichment and metagenomics approach, assembled, and quantified to describe the composition of the viral community. Comparison of the bacterial alpha- and beta-diversity measures revealed that the gut bacteriome of individuals with LADA resembled that of individuals with T2D. Yet, specific genera were found to differ in abundance in individuals with LADA compared with T1D and T2D, indicating that LADA has unique taxonomical features. The virome composition reflected the stability of the most dominant order Caudovirales and the families Siphoviridae, Podoviridae, and Inoviridae, and the dominant family Microviridae. Further studies are needed to confirm these findings.

Early integration of basic palliative care in cancer: scoping review of cross-sectorial models - components, facilitators, barriers.

BACKGROUND: Shared care between oncology specialists and general practice regarding the delivery of palliative care (PC) is necessary to meet the demands for a cohesive PC. The primary objective of this study is to investigate models of cross-sectorial integration between primary care and oncology specialists that have been developed to promote early and basic PC and factors influencing the process. METHOD: A scoping review was conducted using publications dated up until April 2023. Searches were conducted in MEDLINE, CINAHL, Embase, Web of Science and ProQuest Dissertations and Theses. Complementary searches were performed via reference lists and grey literature. Explicit early PC models aimed at patients with cancer aged ≥18 years with healthcare professionals from primary care and oncology constituted the inclusion criteria. The screening of the papers was performed independently by two reviewers. The reporting adheres to the extension for scoping reviews of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. RESULTS: The search provided 5630 articles of which six met the eligibility criteria, each describing a different model of early and cross-sectorial, integrated PC. 12 active components were identified. Education of staff as well as good communication and cooperation skills are essential factors to succeed with integrated, early PC. CONCLUSION: Integration of PC between general practice and oncology specialists has potential. The components of basic PC have been established. Factors known to influence the process are trust, communication and a common goal. Further research is required into strategies for approaching different levels of integration.

Telemetric ICP monitoring in children: a national questionnaire-based study.

PURPOSE: Telemetric monitoring of intracranial pressure (ICP) facilitates long-term measurements and home monitoring, thus potentially reducing diagnostic imaging and acute hospital admissions in favour of outpatient appointments. Especially in paediatric patients, telemetric ICP monitoring requires a high level of collaboration and compliance from patients and parents. In this study, we aim to systematically investigate (1) patient and parent perception of telemetric ICP system utility and (2) hospital contact history and thus the potential cost-benefit of telemetric ICP monitoring in paediatric patients with a cerebrospinal fluid disorder. METHODS: We conducted a nationwide questionnaire study, including paediatric patients with either a current or previous telemetric ICP sensor and their parents. Additionally, a retrospective review of electronic health records for all included children was performed. RESULTS: We included 16 children (age range 3-16 years), with a total of 41 telemetric ICP sensors implanted. Following sensor implantation, the frequency of telephone contacts and outpatient visits increased. No corresponding decrease in hospital admissions or total length of stay was found. The telemetric ICP sensor provided most parents with an improved sense of security and was seen as a necessary and valuable tool in treatment guidance. The size and shape of the sensor itself were reported as disadvantages, while the external monitoring equipment was reported as easy to use but too large and heavy for a child to carry. CONCLUSION: Though, in quantitative terms, there was no cost-benefit of the telemetric ICP sensor, it contributed to extended parental involvement and a sense of improved safety.

Protocol for a prospective multicentre cohort study to address the question whether diabetes and its management is still a risk factor in fast-track joint arthroplasty.

INTRODUCTION: Perioperative glycaemic control is important. However, the complexity of guidelines for perioperative diabetes management is complicated due to different and novel antihyperglycaemic medications, limited procedure-specific data and lack of data from implemented fast-track regimens which otherwise are known to reduce morbidity and glucose homeostasis disturbances. Consequently, outcome in patients with diabetes mellitus (DM) after surgery and the influence of perioperative diabetes management on postoperative recovery remains poorly understood. METHODS AND ANALYSIS: A prospective observational multicentre study involving 8 arthroplasty centres across Denmark with a documented implemented fast-track programme (median length of hospitalisation (LOS) 1 day). We will collect detailed perioperative data including preoperative haemoglobin A1c and antidiabetic treatment in 1400 unselected consecutive patients with DM undergoing hip and knee arthroplasty from September 2022 to December 2025, enrolled after consent. Follow-up duration is 90 days after surgery. The primary outcome is the proportion of patients with DM with LOS >4 days and 90-day readmission rate after fast-track total hip arthroplasty (THA), total knee arthroplasty (TKA) and unicompartmental knee arthroplasty (UKA). The secondary outcome is the association between perioperative diabetes treatment and LOS >2 days, 90-day readmission rate, other patient demographics and Comprehensive Complication Index for patients with DM after THA/TKA/UKA in a fast-track regimen. ETHICS AND DISSEMINATION: The study will follow the principles of the Declaration of Helsinki and ICH-Good Clinical Practice guideline. Ethical approval was not necessary as this is a non-interventional observational study on current practice. The trial is registered in the Region of Southern Denmark and on ClinicalTrials.gov. The main results and all substudies of this trial will be published in peer-reviewed international medical journals. TRIAL REGISTRATION NUMBER: NCT05613439.

The association of cardiometabolic, diet and lifestyle parameters with plasma glucagon-like peptide-1: An IMI DIRECT study.

CONTEXT: The role of glucagon-like peptide-1(GLP-1) in Type 2 diabetes (T2D) and obesity is not fully understood. OBJECTIVE: We investigate the association of cardiometabolic, diet and lifestyle parameters on fasting and postprandial GLP-1 in people at risk of, or living with, T2D. METHOD: We analysed cross-sectional data from the two Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) cohorts, cohort 1(n=2127) individuals at risk of diabetes; cohort 2 (n=789) individuals with new-onset of T2D. RESULTS: Our multiple regression analysis reveals that fasting total GLP-1 is associated with an insulin resistant phenotype and observe a strong independent relationship with male sex, increased adiposity and liver fat particularly in the prediabetes population. In contrast, we showed that incremental GLP-1 decreases with worsening glycaemia, higher adiposity, liver fat, male sex and reduced insulin sensitivity in the prediabetes cohort. Higher fasting total GLP-1 was associated with a low intake of wholegrain, fruit and vegetables inpeople with prediabetes, and with a high intake of red meat and alcohol in people with diabetes. CONCLUSION: These studies provide novel insights into the association between fasting and incremental GLP-1, metabolic traits of diabetes and obesity, and dietary intake and raise intriguing questions regarding the relevance of fasting GLP-1 in the pathophysiology T2D.

Radiographic findings in patients suspected of subacromial impingement syndrome: prevalence and reliability.

OBJECTIVE: Aims were to (i) report prevalence and (ii) evaluate reliability of the radiographic findings in examinations of patients suspected of subacromial impingement syndrome (SIS), performed before a patient's first consultation at orthopaedic department. MATERIALS AND METHODS: This cross-sectional study examined radiographs from 850 patients, age 18 to 63 years, referred to orthopaedic clinic on suspicion of SIS. Prevalence (%) of radiographic findings were registered. Inter- and intrarater reliability was analysed using expected and observed agreement (%), kappa coefficients, Bland-Altman plots, or intraclass coefficients. RESULTS: A total of 850 patients with a mean age of 48.2 years (SD = 8.8) were included. Prevalence of the radiographic findings was as follows: calcification 24.4%, Bigliani type III (hooked) acromion 15.8%, lateral/medial acromial spurs 11.1%/6.6%, acromioclavicular osteoarthritis 12.0%, and Bankart/Hill-Sachs lesions 7.1%. Inter- and intrarater Kappa values for most radiographic findings ranged between 0.40 and 0.89; highest values for the presence of calcification (0.85 and 0.89) and acromion type (0.63 and 0.66). The inter- and intrarater intraclass coefficients ranged between 0.41 and 0.83; highest values for acromial tilt (0.79 and 0.83) and calcification area (0.69 and 0.81). CONCLUSION: Calcification, Bigliani type III (hooked) acromion, and acromioclavicular osteoarthritis were prevalent findings among patients seen in orthopaedic departments on suspicion of SIS. Spurs and Bankart/Hill-Sachs lesions were less common. Optimal reliabilities were found for the presence of calcification, calcification area, and acromial tilt. Calcification qualities, acromion type, lateral spur, and acromioclavicular osteoarthritis showed suboptimal reliabilities. Newer architectural measures (acromion index and lateral acromial angle) performed well with respect to reliability.

Infections increase the risk of decompensation and death in patients with early alcohol-related liver disease.

Background & Aims: Infections are frequent in patients with cirrhosis and worsen prognosis. We evaluated the incidence of infections and their impact on decompensation and death in patients with early alcohol-related liver disease (ALD) during long-term follow-up. Methods: We performed a prospective cohort study of patients in secondary care with a history of excess alcohol intake, no prior decompensation, and with liver biopsies along with clinical investigations conducted at baseline. During follow-up, we reviewed the patients' electronic healthcare records for cases of infections, hospitalizations, transient elastography measurements, decompensations, all-cause mortality, and alcohol intake. Results: We included 461 patients with a mean age of 56±10 years (76% males; fibrosis stage F0-1/F2/F3-4 = 259/107/93 [56%/23%/20%]). During a median follow-up of 4.5 years (IQR 2.9-6.3), 134 patients (29%) developed a total of 312 infections, most frequently pneumonia (106/312, 34%) and urinary tract infections (57/312, 18%). Excessive alcohol intake during follow-up, smoking ≥30 pack years, MELD score and elevated liver stiffness during follow-up were independent predictors of infections. Patients who developed at least one infection had a significantly increased risk of subsequent decompensation (hazard ratio 4.98, 95% CI 2.47-10.03) and death (hazard ratio 8.24, 95% CI 4.65-14.59). Infections increased the risk of decompensation and death independently of baseline fibrosis stage, age, gender, and MELD score. Conclusions: Almost one-third of patients with early ALD develop an infection, which worsens their prognosis by increasing the risk of decompensation and death. The risk of infections increases with liver disease severity and ongoing harmful use of alcohol. Impact and implications: This study reveals that infections significantly worsen the prognosis of patients with early alcohol-related liver disease (ALD), increasing the likelihood of decompensation and death by up to eight times. These findings, pertinent to healthcare providers, researchers, and policymakers, emphasize the importance of early prevention and management of infections in patients with ALD, even those in early stages who may be asymptomatic. It was observed that nearly one-third of patients with early-stage ALD developed infections over 4.5 years, with risk factors including alcohol overuse, smoking, and higher MELD scores. The research underscores the critical need to incorporate these insights into clinical practice and public health policies to improve patient outcomes and mitigate the impact of infections in patients with ALD.