Boehringer Ingelheim (Sweden)

While hundreds of thousands of new chemical reactions are reported annually, efficient use of this vast collection of synthetic knowledge remains a persistent challenge in modern chemistry. Recent applications of large language models (LLMs) have shown promise, but systems that reliably work for de novo compounds and molecular transformations have remained elusive. Here we introduce MOSAIC (Multiple Optimized Specialists for AI-Driven Chemical Prediction), a computational framework that enables chemists to harness the collective knowledge of millions of reaction protocols. In contrast to existing approaches relying on agentic models, MOSAIC leverages the open-source Llama3.1-8B-instruct architecture. By training 2,489 specialized chemical experts on Voronoi-clustered reaction spaces, we establish a scalable paradigm that delivers reproducible and human-readable experimental protocols for complex syntheses. Experimental validation demonstrates MOSAIC's ability to predict and execute previously unreported transformations, including challenging reactions via Buchwald-Hartwig amination, Suzuki coupling, and olefin metathesis. We validate this approach through the successful synthesis of over 35 novel compounds spanning pharmaceuticals, materials, agrochemicals, and cosmetics. This framework establishes a new relationship between computational and experimental chemistry, providing a foundation for accelerated chemical discovery across disciplines.

Abstract Obesity and cardiometabolic disease often, but not always, coincide. Distinguishing sub-populations within which cardiometabolic risk diverges from the risk expected for a given body mass index (BMI) may facilitate precision prevention of cardiometabolic diseases. Accordingly, we performed unsupervised clustering in four European population-based cohorts (N ~ 173K). We detected five discordant profiles consisting of individuals with cardiometabolic biomarkers higher or lower than expected given their BMI, in total representing ~20% of the total population. Persons with discordant profiles differed from concordant individuals in prevalence and future risk of major adverse cardiovascular events (MACE) and diabetes. Subtle BMI-discordances in biomarkers affected disease risk. For instance, a 10% higher probability of having a discordant lipid profile was associated with a 5% higher risk of MACE (HR in women: 1.05, 95% CI: 1.03, 1.06, p = 4.19x10-10; HR in men: 1.05, 95% CI: 1.04, 1.06, p= 9.33x10-14). Multivariate prediction models for MACE and diabetes performed better when incorporating discordant profile information (likelihood ratio test P < 0.001). This enhancement represents an additional net benefit of 4 to 15 additional correct interventions, and 37 to 135 additional unnecessary interventions correctly avoided for every 10,000 individuals tested.

AimsTo evaluate effectiveness and healthcare resource utilization (HCRU) of empagliflozin versus dipeptidyl peptidase‐4 inhibitors (DPP‐4i) in Swedish clinical practice, as part of the EMPRISE EU study (EUPAS27606, NCT03817463).Materials and MethodsA non‐interventional, cohort study using retrospectively collected data from Swedish national registries. Adults with type 2 diabetes newly initiated on empagliflozin or DPP‐4i from May 2014 to December 2018 were matched 1:1 using propensity scores based on >180 covariates. Cardiovascular outcomes included hospitalization for heart failure (HHF), all‐cause mortality (ACM), myocardial infarction (MI), stroke and cardiovascular mortality (CVM), as well as their composite outcomes. Renal outcomes included end‐stage renal disease (ESRD), estimated glomerular filtration rate (eGFR) decline to <60 ml/min/1.73 m2 and progression to micro/macroalbuminuria. HCRU outcomes were also assessed. Comparisons were done using Cox proportional hazards and Poisson regression models.ResultsOverall, 15,785 matched‐pairs were identified, with a mean follow‐up of 6.4 and 9.7 months for patients initiating empagliflozin versus DPP‐4i, respectively. Empagliflozin was associated with significant reduction in rates of HHF (hazard ratio [HR] = 0.67; 95% confidence interval: 0.49‐0.91), ACM (HR = 0.53; 0.41‐0.68), HHF + ACM (HR = 0.59; 0.48‐0.73), MI + stroke + ACM (HR = 0.68; 0.57‐0.81), CVM (HR = 0.46; 0.29‐0.73), HHF + CVM (HR = 0.61; 0.47‐0.79) and MI + stroke + CVM (HR = 0.79; 0.63‐0.98) versus DPP‐4i. Empagliflozin also reduced the rates of ESRD (HR = 0.13; 0.03‐0.57) and eGFR decline (HR = 0.83; 0.70‐0.99). Regarding HCRU, empagliflozin was associated with lower risk of first inpatient stay (HR = 0.87; 0.81‐0.93), and lower rate of inpatient and outpatient visits (rate ratio [RR] = 0.85; 0.80‐0.89 and RR = 0.96; 0.94‐0.98) than DPP‐4i.ConclusionsEmpagliflozin treatment compared to DPP‐4i reduced cardiorenal events and overall mortality, which may explain lower HCRU among empagliflozin users in Sweden.

Porcine reproductive and respiratory syndrome virus (PRRSV) causes significant economic losses to the swine industry worldwide. Little is known regarding the epidemiology of this infection in tropical countries. To address this problem in Costa Rica, a seroepidemiological study was carried out in two phases. In the first phase, a pilot study was conducted in nine farms with the clinical diagnosis of PRRSV. In total, 265 pig serum samples were collected from animals ranging in age from 1 to 15 weeks of age. This study aimed to establish the duration of maternal immunity in piglets, to identify the period of viremia, and to determine when seroconversion occurs. In the second phase, a cross-sectional serology study was performed on a representative sample of the Costa Rican national herds in the second phase. The twenty-five selected farms represent all provinces and were classified according to herd size (100 to 2000 sows). In each farm, pigs aged 8, 10, and 12 weeks were sampled, as well as gilts based on the pilot study. In total 1281 pigs were sampled across all 25 farms. The aim of the cross-sectional study was to quantify the seroprevalence of PRRSV in Costa Rican pig farms and to describe its geographical distribution in this tropical country. The prevalence of positive farms was 44% (11/25), and these farms were located in six of the seven provinces of Costa Rica. Overall, 58% (344/596) of the pigs were seropositive to PRRSV. The age of the pigs and the ecozone where farms were located were significantly related with PRRSV seroprevalence in animals and herds, respectively.

Aim. To analyze clinical characteristics of patients with nonvalvular atrial fibrillation (AF) in the Russian population, enrolled in the GLORIA-AF registry phase 2, depending on the antithrombotic therapy received, and to assess the potential for patient retention with dabigatran during a 2-year follow-up.Material and methods. In the Russian Federation, 408 patients were included in the second phase of GLORIA-AF which is a global prospective observational registry of newly diagnosed patients with AF. The patient characteristics are presented depending on received antithrombotic therapy (dabigatran, factor Xa inhibitors, vitamin K antagonist, antiplatelet agents, or no antithrombotic therapy), with a dabigatran dosing regimen of either 110 mg or 150 mg twice daily. Duration of patient retention on dabigatran therapy was also analyzed during a 2-year follow-up.Results. Of the 405 patients with recently diagnosed nonvalvular AF, 358 (88%) received oral anticoagulants (OAC), and 47 (12%) patients received antiplatelet drugs or received no antithrombotic therapy. Most patients were treated with dabigatran (n=275, 68%), and 75 (19%) patients received vitamin K antagonist. Clinical and demographic characteristics of patients receiving dabigatran were comparable with those in the general group of the Russian patients. The mean age was 63,5 years. The most common comorbidities in Russian patients receiving dabigatran were hypertension (93%), congestive heart failure (57%), coronary artery disease (35%). It is noteworthy that 12% and 10% of patients had a previous myocardial infarction and stroke, respectively. The mean CHA2DS2-VASc score for stroke risk for these patients was 3,2; 88% of patients had a high stroke risk (score of &gt;2). Of the 275 patients with AF who received dabigatran therapy, 164 (60%) patients received dabigatran at the dose of 150 mg twice daily, and 111 (40%) patients received 110 mg twice daily. Dabigatran doses of 110 mg twice daily were more frequently prescribed for female patients aged 65 years or older and patients with a previous coronary events and impaired renal function, who had a higher CHA2DS2-VASc score for stroke risk. There was a higher proportion of AF patients with marked symptoms in the dabigatran 150 mg twice daily group. A median duration of treatment with dabigatran with the initial dosing regimen was 24 months. The estimated dabigatran therapy retention rate was 0,87, 0,81 and 0,73 after 6, 12 and 24 months of follow-up, respectively.Conclusion. In the Russian Federation, patients with newly diagnosed AF who have an increased risk of stroke are more likely to receive OAC therapy, such as direct thrombin inhibitor (dabigatran), compared to the global cohort of the GLORIA AF Registry Program. Patients in the Russian cohort receiving dabigatran differ from the global cohort of patients by greater comorbidity. At the same time, patients receiving reduced doses of dabigatran, both in the Russian Federation and in the global Registry, are characterized by a greater proportion of patients aged &gt;75 years, a higher incidence of previous myocardial infarction, coronary artery disease, heart failure, impaired renal function, higher CHA2DS2-VASc score for stroke risk. The potential dabigatran therapy retention rate after 24 months in the Russian Federation and in the global cohort was high and amounted to about 70%.

Abstract BackgroundThe study characterizes safety, tolerability, pharmacokinetic and pharmacodynamic profiles of single rising doses of the 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD1) inhibitor BI 187004 in healthy men with overweight or obesity.MethodsThis was a randomized, double-blind, parallel group, placebo-controlled study with administration of 2.5-360 mg BI 187004 or placebo once daily as single dose in 72 healthy volunteers with overweight or obesity.Assessments included 11beta-HSD1 inhibition in the liver (assessed indirectly by urinary tetrahydrocortisol/tetrahydrocotisone ratio) and in subcutaneous adipose tissue ex vivo and determination of hypothalamus-pituitary-adrenal axis hormones.ResultsBI 187004 was well tolerated and safe in all tested dose groups. The incidence of drug-related adverse events was 16.7% (n=9) for all 9 BI 187004 dose groups and 5.9% (n=1) for placebo. All treatment groups were similar concerning kind and intensity of adverse events. No clinically relevant deviations in clinical laboratory or ECG parameters were reported. Exposure of BI 187004 increased non‑proportionally over the entire dose range tested. The geometric mean apparent terminal half-life decreased from 33.5h (5 mg) to 14.5h (160 mg) remaining stable up to 360 mg. Renal excretion of BI 187004 was low (3-5%). Urinary tetrahydrocortisol/tetrahydrocotisone ratio decreased, indicating liver 11beta-HSD1 inhibition. Median inhibition of 11beta-HSD1 in subcutaneous adipose tissue biopsies following single dosing ranged from 86.8% (10 mg) to 99.5% (360 mg) after 10h and from 59.4% (10 mg) to 98.6% (360 mg) after 24h. ConclusionsBI 187004 as single dose was safe and well tolerated and is suitable for once daily dosing. There was significant, sustained 11beta-HSD1 inhibition in liver and adipose tissue. Trial registry number: ClinicalTrials.gov, NCT01587417, registered on 26-Apr-2012, https://clinicaltrials.gov/ct2/show/study/NCT01587417