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Introduction : Effective postoperative pain management is imperative in total hip arthroplasty (THA) to enable early mobilization and accelerate recovery pathways. This study investigated the patterns of inpatient opioid consumption following THA and identified the factors associated with increased opioid usage. Methods : In this large-scale, single-institution study, we analyzed data from 1,867 primary THAs between April 2019 and July 2023. We collected data on demographics, length of stay (LOS), type of anaesthesia, Post Anaesthesia Care Unit (PACU) admissions, 30-day readmissions, total opioid consumption (MME; morphine milligram equivalents), implant fixation techniques, surgical characteristics and pre- and postoperative haemoglobin (Hb) levels. Factors associated with increased opioid consumption (patients in the ≥ 75th percentile of inpatient opioid consumption; MME ≥ 211.9 mg) were identified through univariate and multivariate logistic regression models. Results : The cohort included 1150 women (61.6%) and 717 men (38.4%). The median inpatient opioid use was 88 mg (IQR = 39.3–211.9). In the univariate model, significant predictors included age, American Society of Anaesthesiologists (ASA) score, manual THA technique, general anaesthesia, pre- and postoperative Hb levels, need for PACU admission and year of surgery. After adjusting for baseline demographics in the hierarchical multivariate logistic regression model, significant predictors of higher opioid utilization were age (OR 0.989 [95% CI 0.981–0.997], p  = 0.01), general anaesthesia (OR 2.386 [95% CI 1.865–3.054], p  < 0.001), PACU admission (OR 2.098 [95% CI 1.310–3.358], p  = 0.002), ASA score (OR 1.492 [95% CI 1.193–1.866], p  < 0.001), postoperative Hb levels (OR 0.981 [95% CI 0.970–0.992], p  < 0.001), and year of surgery (OR 0.638 [95% CI 0.579–0.703], p  < 0.001) indicating that later years were associated with lower odds of high opioid consumption). Discussion : Younger age, higher ASA scores, lower postoperative haemoglobin, the need for PACU admission and general anaesthesia were significantly associated with increased opioid consumption following THA. Recognizing these factors can facilitate the development of tailored postoperative pain management protocols, enabling targeted interventions that minimize opioid reliance while enhancing recovery.

Aims/hypothesisIndividuals with type 2 diabetes have aberrant intestinal microbiota. However, recent studies suggest that metformin alters the composition and functional potential of gut microbiota, thereby interfering with the diabetes-related microbial signatures. We tested whether specific gut microbiota profiles are associated with prediabetes (defined as fasting plasma glucose of 6.1–7.0 mmol/l or HbA1c of 42–48 mmol/mol [6.0–6.5%]) and a range of clinical biomarkers of poor metabolic health.MethodsIn the present case–control study, we analysed the gut microbiota of 134 Danish adults with prediabetes, overweight, insulin resistance, dyslipidaemia and low-grade inflammation and 134 age- and sex-matched individuals with normal glucose regulation.ResultsWe found that five bacterial genera and 36 operational taxonomic units (OTUs) were differentially abundant between individuals with prediabetes and those with normal glucose regulation. At the genus level, the abundance of Clostridium was decreased (mean log2 fold change −0.64 (SEM 0.23), padj = 0.0497), whereas the abundances of Dorea, [Ruminococcus], Sutterella and Streptococcus were increased (mean log2 fold change 0.51 (SEM 0.12), padj = 5 × 10−4; 0.51 (SEM 0.11), padj = 1 × 10−4; 0.60 (SEM 0.21), padj = 0.0497; and 0.92 (SEM 0.21), padj = 4 × 10−4, respectively). The two OTUs that differed the most were a member of the order Clostridiales (OTU 146564) and Akkermansia muciniphila, which both displayed lower abundance among individuals with prediabetes (mean log2 fold change −1.74 (SEM 0.41), padj = 2 × 10−3 and −1.65 (SEM 0.34), padj = 4 × 10−4, respectively). Faecal transfer from donors with prediabetes or screen-detected, drug-naive type 2 diabetes to germfree Swiss Webster or conventional C57BL/6 J mice did not induce impaired glucose regulation in recipient mice.Conclusions/interpretationCollectively, our data show that individuals with prediabetes have aberrant intestinal microbiota characterised by a decreased abundance of the genus Clostridium and the mucin-degrading bacterium A. muciniphila. Our findings are comparable to observations in overt chronic diseases characterised by low-grade inflammation.

Impaired gut barrier function may lead to progression of liver fibrosis in people with alcohol-related liver disease. The postbiotic ReFerm® can lower gut barrier permeability and may thereby  reduce fibrosis formation. Here, we report the results from an open-labelled, single centre randomized controlled trial where 56 patients with advanced, compensated, alcohol-related liver disease were assigned 1:1 to receive either ReFerm® ( n  = 28) or standard nutritional support (Fresubin®, n  = 28) for 24 weeks. The primary outcome was a ≥ 10% reduction of the fibrosis formation marker alpha-smooth muscle actin in liver biopsies, assessed by a blinded pathologist using automated digital imaging analysis. Paired liver biopsies meeting quality criteria for the primary outcome were available for 40 participants (ReFerm®, n  = 21 and Fresubin®, n  = 19). This reduction was observed in 29% of patients receiving ReFerm®, compared to 14% with Fresubin® (OR = 2.40; 95% CI 0.63 to 9.16; p  = 0.200). No treatment-related serious adverse events occurred. Our findings suggest that ReFerm® may reduce liver fibrosis by enhancing gut barrier function, potentially preventing the progression of alcohol-related liver disease. Impaired gut barrier function is a central driver of alcohol-related liver disease. This study indicates that the postbiotic ReFerm® improves gut barrier function and reduce liver stiffness and liver fibrosis, suggesting the gut barrier function as a potential treatment target.

Summary We consider reconciliation of wind power forecasts in a spatial hierarchy with three aggregation levels. We produce base forecasts for the bottom level consisting of 407 substations (connection points for local groups of wind turbines). State‐of‐the‐art forecasts from a commercial forecast provider are available for the middle and top levels, which consist of 15 regions and the entire Western Denmark (DK1), respectively. We find that the accuracy of the total forecast can be improved through spatial reconciliation, even with a relatively simple model used at the lowest level of the hierarchy. Computing the base forecasts for the substations using wind speed as the only predictor, the RMSE of the DK1 forecast is reduced by 20.5%, while the RMSE of the regional forecasts is reduced by 4.7%, on average, through reconciliation. The increase in accuracy is partly due to reduced errors in the individual regional forecasts and partly due to reduced residual correlation between the reconciled regional forecasts. We test adaptive estimation of the covariance matrix of the base forecast errors and find that it has a limited impact on the accuracy, hinting toward a time‐stable covariance structure.

Information on the pharmacokinetics (PK) and pharmacodynamics (PD) of orally administered cannabis‐based medicine (CBM) in capsule formulation in patient populations is sparse. In this exploratory study, we aimed to evaluate the PK and PD in a probable steady state of CBM in neuropathic pain and spasticity in a population of patients with multiple sclerosis (MS). Of 134 patients participating in a randomized, double‐blinded, placebo‐controlled, trial, 23 patients with MS (17 female) mean age 52 years (range 21–67) were enrolled in this substudy. They received oral capsules containing Δ9‐tetrahydrocannabinol (THC, n = 4), cannabidiol (CBD, n = 6), a combination (THC&CBD, n = 4), or placebo (n = 9). Maximum doses were 22.5 mg (THC) and 45 mg (CBD) a day divided into three administrations. PD parameters were evaluated for pain and spasticity. Blood samples were analyzed using an ultra‐high‐performance liquid chromatography–tandem mass spectrometer after protein precipitation and phospholipid removal. PK parameters were estimated using computerized modeling. The variation in daily dose and PK between individuals was considerable in a steady state, yet comparable with previous reports from healthy controls. Based on a simulation of the best model, the estimated PK parameters (mean) for THC (5 mg) were Cmax 1.21 ng/mL, Tmax 2.68 h, and half‐life 2.75 h, and for CBD (10 mg) were Cmax 2.67 ng/mL, Tmax 0.10 h, and half‐life 4.95 h, respectively. No effect was found on the PD parameters, but the placebo response was considerable. More immediate adverse events were registered in the active treatment groups compared with the placebo group.

Background Reports of dual carriers of pathogenic BRCA1 variants in trans are extremely rare, and so far, most individuals have been associated with a Fanconi Anemia-like phenotype. Methods We identified two families with a BRCA1 in-frame exon 20 duplication (Ex20dup). In one male individual, the variant was in trans with the BRCA1 frameshift variant c.2475delC p.(Asp825Glufs*21). We performed splicing analysis and used a transcription activation domain (TAD) assay to assess the functional impact of Ex20dup. We collected pedigrees and mapped the breakpoints of the duplication by long- and short-read genome sequencing. In addition, we performed a mitomycin C (MMC) assay from the dual carrier using cultured lymphoblastoid cells. Results Genome sequencing and RNA analysis revealed the BRCA1 exon 20 duplication to be in tandem. The duplication was expressed without skipping any one of the two exon 20 copies, resulting in a lack of wild-type transcripts from this allele. TAD assay indicated that the Ex20dup variant has a functional level similar to the well-known moderate penetrant pathogenic BRCA1 variant c.5096G > A p.(Arg1699Gln). MMC assay of the dual carrier indicated a slightly impaired chromosomal repair ability. Conclusions This is the first reported case where two BRCA1 variants with demonstrated functional impact are identified in trans in a male patient with an apparently normal clinical phenotype and no BRCA1- associated cancer. The results pinpoint a minimum necessary BRCA1 protein activity to avoid a Fanconi Anemia-like phenotype in compound heterozygous status and yet still predispose carriers to hormone-related cancers. These findings urge caution when counseling families regarding potential Fanconi Anemia risk. Furthermore, prudence should be taken when classifying individual variants as benign based on co-occurrence in trans with well-established pathogenic variants.

Ketone bodies are neuroprotective in neurological disorders such as epilepsy. We randomly studied nine healthy human subjects twice-with and without continuous infusion of 3-hydroxybutyrate-to define potential underlying mechanisms, assessed regionally (parietal, occipital, temporal, cortical grey, and frontal) by PET scan. During 3-hydroxybutyrate infusions concentrations increased to 5.5±0.4 mmol/l and cerebral glucose utilisation decreased 14%, oxygen consumption remained unchanged, and cerebral blood flow increased 30%. We conclude that acute 3-hydroxybutyrate infusion reduces cerebral glucose uptake and increases cerebral blood flow in all measured brain regions, without detectable effects on cerebral oxygen uptake though oxygen extraction decreased. Increased oxygen supply concomitant with unchanged oxygen utilisation may contribute to the neuroprotective effects of ketone bodies.

ObjectiveTo investigate whether a whole grain diet alters the gut microbiome and insulin sensitivity, as well as biomarkers of metabolic health and gut functionality.Design60 Danish adults at risk of developing metabolic syndrome were included in a randomised cross-over trial with two 8-week dietary intervention periods comprising whole grain diet and refined grain diet, separated by a washout period of ≥6 weeks. The response to the interventions on the gut microbiome composition and insulin sensitivity as well on measures of glucose and lipid metabolism, gut functionality, inflammatory markers, anthropometry and urine metabolomics were assessed.Results50 participants completed both periods with a whole grain intake of 179±50 g/day and 13±10 g/day in the whole grain and refined grain period, respectively. Compliance was confirmed by a difference in plasma alkylresorcinols (p<0.0001). Compared with refined grain, whole grain did not significantly alter glucose homeostasis and did not induce major changes in the faecal microbiome. Also, breath hydrogen levels, plasma short-chain fatty acids, intestinal integrity and intestinal transit time were not affected. The whole grain diet did, however, compared with the refined grain diet, decrease body weight (p<0.0001), serum inflammatory markers, interleukin (IL)-6 (p=0.009) and C-reactive protein (p=0.003). The reduction in body weight was consistent with a reduction in energy intake, and IL-6 reduction was associated with the amount of whole grain consumed, in particular with intake of rye.ConclusionCompared with refined grain diet, whole grain diet did not alter insulin sensitivity and gut microbiome but reduced body weight and systemic low-grade inflammation.Trial registration number NCT01731366; Results.

IntroductionThe cornerstone in the management of type 2 diabetes (T2D) is lifestyle modification including a healthy diet, typically one in which carbohydrate provides 45%–60% of total energy intake (E%). Nevertheless, systematic reviews and meta-analyses of trials with low carbohydrate diets (which are increased in protein and/or fat) for T2D have found improved glycaemic control in the first months relative to comparator diets with higher carbohydrate content. Studies lasting ≥1 year are inconclusive, which could be due to decreased long-term dietary adherence. We hypothesise that glucometabolic benefits can be achieved following 12 months of carbohydrate-restricted dieting, by maximising dietary adherence through delivery of meal kits, containing fresh, high-quality ingredients for breakfast, dinner and snacks, combined with nutrition education and counselling.Methods and analysisThis protocol describes a 12-month investigator-initiated randomised controlled, open-label, superiority trial with two parallel groups that will examine the effect of a carbohydrate-reduced high-protein (CRHP) diet compared with a conventional diabetes (CD) diet on glucometabolic control (change in glycated haemoglobin being the primary outcome) in 100 individuals with T2D and body mass index (BMI) >25 kg/m2. Participants will be randomised 1:1 to receive either the CRHP or the CD diet (comprised 30/50 E% from carbohydrate, 30/17 E% from protein and 40/33 E% from fat, respectively) for 12 months delivered as meal kits, containing foods covering more than two-thirds of the participants’ estimated daily energy requirements for weight maintenance. Adherence to the allocated diets will be reinforced by monthly sessions of nutrition education and counselling from registered clinical dietitians.Ethics and disseminationThe trial has been approved by the National Committee on Health Research Ethics of the Capital Region of Denmark. The trial will be conducted in accordance with the Declaration of Helsinki. Results will be submitted for publication in international peer-reviewed scientific journals.Trial registration number NCT05330247.Protocol versionThe trial protocol was approved on 9 March 2022 (study number: H-21057605). The latest version of the protocol, described in this manuscript, was approved on 23 June 2023.

New lineages of SARS-CoV-2 are of potential concern due to higher transmissibility, risk of severe outcomes, and/or escape from neutralizing antibodies. Lineage B.1.1.7 (the Alpha variant) became dominant in early 2021, but the association between transmissibility and risk factors, such as age of primary case and viral load remains poorly understood. Here, we used comprehensive administrative data from Denmark, comprising the full population (January 11 to February 7, 2021), to estimate household transmissibility. This study included 5,241 households with primary cases; 808 were infected with lineage B.1.1.7 and 4,433 with other lineages. Here, we report an attack rate of 38% in households with a primary case infected with B.1.1.7 and 27% in households with other lineages. Primary cases infected with B.1.1.7 had an increased transmissibility of 1.5–1.7 times that of primary cases infected with other lineages. The increased transmissibility of B.1.1.7 was multiplicative across age and viral load. Establishing the relative transmissibility of emerging variants of SARS-CoV-2 is key for pandemic management. Here, the authors use full-population administrative data from Denmark linked to PCR test results and estimate that the Alpha variant was ~60% higher than other strains circulating in early 2021.