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Digital twin technology offers significant benefits for addressing fracture non-unions in orthopedic trauma surgery, particularly in cases requiring revision surgery. In this study, we developed a clinically applicable digital twin workflow that integrates patient-specific imaging, motion capture, musculoskeletal modeling, and finite element simulation. We applied this workflow to five real patient cases involving different anatomical sites and treatment strategies, including implant modification, augmentative fixation, and corrective osteotomy. Each case was virtually reconstructed to evaluate mechanical conditions before and after revision surgery. The results demonstrated that digital twins can predict improvements in implant stress distribution and fracture strain states, offering valuable insights for optimizing surgical decisions. This work highlights the feasibility of digital twins and their clinical value in supporting individualized revision strategies, laying the foundation for their broader use in trauma care. .

Hyperpolarization-activated, cyclic nucleotide-gated cation currents, termed Ifor Ih, are generated by four members of the hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channel family. These currents have been proposed to contribute to several functions including pacemaker activity in heart and brain, control of resting potential, and neuronal plasticity. Transcripts of the HCN4 isoform have been found in cardiomyocytes and neurons, but the physiological role of this channel is unknown. Here we show that HCN4 is essential for the proper function of the developing cardiac conduction system. In wild-type embryos, HCN4 is highly expressed in the cardiac region where the early sinoatrial node develops. Mice lacking HCN4 channels globally, as well as mice with a selective deletion of HCN4 in cardiomyocytes, died between embryonic days 9.5 and 11.5. On average, Ifin cardiomyocytes from mutant embryos is reduced by 85%. Hearts from HCN4-deficient embryos contracted significantly slower compared with wild type and could not be stimulated by cAMP. In both wild-type and HCN4-/-mice, cardiac cells with \"primitive\" pacemaker action potentials could be found. However, cardiac cells with \"mature\" pacemaker potentials, observed in wild-type embryos starting at day 9.0, were not detected in HCN4-deficient embryos. Thus, HCN4 channels are essential for the proper generation of pacemaker potentials in the emerging sinoatrial node.

During the first wave of Covid-19 infections in Germany in April 2020, clinics reported a shortage of filtering face masks with aerosol retention> 94% (FFP2 & 3, KN95, N95). Companies all over the world increased their production capacities, but quality control of once-certified materials and masks came up short. To help identify falsely labeled masks and ensure safe protection equipment, we tested 101 different batches of masks in 993 measurements with a self-made setup based on DIN standards. An aerosol generator provided a NaCl test aerosol which was applied to the mask. A laser aerosol spectrometer measured the aerosol concentration in a range from 90 to 500 nm to quantify the masks’ retention. Of 101 tested mask batches, only 31 batches kept what their label promised. Especially in the initial phase of the pandemic in Germany, we observed fluctuating mask qualities. Many batches show very high variability in aerosol retention. In addition, by measuring with a laser aerosol spectrometer, we were able to show that not all masks filter small and large particles equally well. In this study we demonstrate how important internal and independent quality controls are, especially in times of need and shortage of personal protection equipment.

The illegal use of explosives by terrorists and other criminals is an increasing issue in public spaces, such as airports, railway stations, highways, sports venues, theaters, and other large buildings. Security in these environments can be achieved by different means, including the installation of scanners and other analytical devices to detect ultra-small traces of explosives in a very short time-frame to be able to take action as early as possible to prevent the detonation of such devices. Unfortunately, an ideal explosive detection system still does not exist, which means that a compromise is needed in practice. Most detection devices lack the extreme analytical sensitivity, which is nevertheless necessary due to the low vapor pressure of nearly all explosives. In addition, the rate of false positives needs to be virtually zero, which is also very difficult to achieve. Here we present an immunosensor system based on kinetic competition, which is known to be very fast and may even overcome affinity limitation, which impairs the performance of many traditional competitive assays. This immunosensor consists of a monolithic glass column with a vast excess of immobilized hapten, which traps the fluorescently labeled antibody as long as no explosive is present. In the case of the explosive 2,4,6-trinitrotoluene (TNT), some binding sites of the antibody will be blocked, which leads to an immediate breakthrough of the labeled protein, detectable by highly sensitive laser-induced fluorescence with the help of a Peltier-cooled complementary metal-oxide-semiconductor (CMOS) camera. Liquid handling is performed with high-precision syringe pumps and chip-based mixing-devices and flow-cells. The system achieved limits of detection of 1 pM (1 ppt) of the fluorescent label and around 100 pM (20 ppt) of TNT. The total assay time is less than 8 min. A cross-reactivity test with 5000 pM solutions showed no signal by pentaerythritol tetranitrate (PETN), 1,3,5-trinitroperhydro-1,3,5-triazine (RDX), and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX). This immunosensor belongs to the most sensitive and fastest detectors for TNT with no significant cross-reactivity by non-related compounds. The consumption of the labeled antibody is surprisingly low: 1 mg of the reagent would be sufficient for more than one year of continuous biosensor operation.

The Pro12Ala polymorphism of the gene encoding the peroxisome proliferator-activated receptor (PPAR)-γ2 has recently been shown to be associated with type 2 diabetes. In the present analysis, we investigated whether PPAR-γ2 Pro12Ala was associated with microvascular complications of type 2 diabetes, such as albuminuria, end-stage renal failure (ESRF), or retinopathy. A total of 445 patients with type 2 diabetes who were enrolled in the Berlin Diabetes Mellitus Study and in whom we determined albuminuria and the presence of ESRF and retinopathy were genotyped for the PPAR-γ2 Pro12Ala polymorphism. We also measured potentially important covariables, such as blood pressure, BMI, duration of diabetes, glycosylated hemoglobin, serum creatinine, and serum lipids. Among 445 patients with type 2 diabetes (mean age 59.3 years), the Pro12Ala genotype distribution was in Hardy-Weinberg equilibrium (P = 0.42). The Ala12 allele frequency was 0.14. With adjustment for covariables, the 118 Ala12 allele carriers had significantly lower urinary albumin excretion (UAE) than the 327 noncarriers (17.1 vs. 25.8 mg/d; P = 0.01). The percentage decrease in UAE observed in PPAR-γ Ala12 allele carriers relative to noncarriers (P = 0.003) rose from 0.2% (P = 0.99) to 54% (P = 0.008) and to 70% (P = 0.01) when the duration of diabetes increased from <10 years to 10-19 years and to ≥ 20 years, respectively. Similarly, the odds ratios of having albuminuria decreased from 1.22 (P = 0.54) to 0.61 (P = 0.23) and to 0.11 (P = 0.007), respectively. Among patients with type 2 diabetes, PPAR-γ2 Ala12 allele carriers had significantly lower UAE and tended to develop overt proteinuria less frequently. These observations suggest a protective effect of the Ala12 allele in relation to diabetic nephropathy.

G/T Substitution in Intron 1 of the UNC13B Gene Is Associated With Increased Risk of Nephropathy in Patients With Type 1 Diabetes David-Alexandre Trégouet 1 , Per-Henrik Groop 2 3 , Steven McGinn 4 , Carol Forsblom 2 3 , Samy Hadjadj 5 6 , Michel Marre 7 8 , Hans-Henrik Parving 9 , Lise Tarnow 10 , Ralph Telgmann 11 , Tiphaine Godefroy 1 , Viviane Nicaud 1 , Rachel Rousseau 1 , Maikki Parkkonen 3 , Anna Hoverfält 3 , Ivo Gut 4 , Simon Heath 4 , Fumihiko Matsuda 4 , Roger Cox 12 , Gbenga Kazeem 13 , Martin Farrall 13 , Dominique Gauguier 13 , Stefan-Martin Brand-Herrmann 11 , François Cambien 1 , Mark Lathrop 4 , Nathalie Vionnet 1 and for the EURAGEDIC Consortium 1 INSERM, Paris, France, and Pierre and Marie Curie-Paris VI University, Paris, France 2 Helsinki University Central Hospital, Department of Medicine, Division of Nephrology, Helsinki, Finland 3 Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum, Helsinki, Finland 4 CEA/Institute of Genomics-National Genotyping Center, Evry, France 5 CHU Poitiers, Department of Diabetology, Poitiers, France 6 INSERM U927, CHU Poitiers, Poitiers, France 7 Assistance Publique des Hôpitaux de Paris, Centre Hospitalier Universitaire Bichat-Claude Bernard, Paris, France 8 Université Paris, INSERM U695, Paris, France 9 University Hospital of Copenhagen, Rigshospitalet, Department of Medical Endocrinology, Copenhagen, Denmark 10 Steno Diabetes Center, Copenhagen, Denmark 11 Leibniz Institute for Arteriosclerosis Research, Department of Molecular Genetics of Cardiovascular Disease, University of Muenster, Muenster, Germany 12 Mammalian Research Council, Mammalian Genetics Unit, Harwell, U.K 13 Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, U.K Corresponding author: Nathalie Vionnet, vionnet{at}cng.fr Abstract OBJECTIVE— Genetic and environmental factors modulate the susceptibility to diabetic nephropathy, as initiating and/or progression factors. The objective of the European Rational Approach for the Genetics of Diabetic Complications (EURAGEDIC) study is to identify nephropathy susceptibility genes. We report molecular genetic studies for 127 candidate genes for nephropathy. RESEARCH DESIGN AND METHODS— Polymorphisms were identified through sequencing of promoter, exon, and flanking intron gene regions and a database search. A total of 344 nonredundant SNPs and nonsynonymous variants were tested for association with diabetic nephropathy (persistent albuminuria ≥300 mg/24 h) in a large type 1 diabetes case/control (1,176/1,323) study from three European populations. RESULTS— Only one SNP, rs2281999, located in the UNC13B gene, was significantly associated with nephropathy after correction for multiple testing. Analyses of 21 additional markers fully characterizing the haplotypic variability of the UNC13B gene showed consistent association of SNP rs13293564 (G/T) located in intron 1 of the gene with nephropathy in the three populations. The odds ratio (OR) for nephropathy associated with the TT genotype was 1.68 (95% CI 1.29–2.19) ( P = 1.0 × 10 −4 ). This association was replicated in an independent population of 412 case subjects and 614 control subjects (combined OR of 1.63 [95% CI 1.30–2.05], P = 2.3 × 10 −5 ). CONCLUSIONS— We identified a polymorphism in the UNC13B gene associated with nephropathy. UNC13B mediates apopotosis in glomerular cells in the presence of hyperglycemia, an event occurring early in the development of nephropathy. We propose that this polymorphism could be a marker for the initiation of nephropathy. However, further studies are needed to clarify the role of UNC13B in nephropathy. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 15 July 2008. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted July 8, 2008. Received January 18, 2008. DIABETES

Purpose Vericiguat reduced clinical endpoints in patients experiencing worsening heart failure in clinical trials, but its implementation outside trials is unclear. Methods This retrospective analysis of longitudinally collected data was based on the IQVIA™ LRx database, which includes ~ 80% of the prescriptions of the 73 million people covered by the German statutory health insurance. Results Between September 2021 and December 2022, vericiguat was initiated in 2916 adult patients. Their mean age was 73 ± 13 years and 28% were women. While approximately 70% were uptitrated beyond 2.5 mg, only 36% reached 10 mg. Median time to up-titration from 2.5 mg to 5 mg was 17 (quartiles: 11–33) days, and from 2.5 to 10 mg 37 (25–64) days, respectively. In 87% of the patients, adherence to vericiguat was high as indicated by a medication possession ratio of  ≥ 80%, and 67% of the patients persistently used vericiguat during the first year. Women and older patients reached the maximal dose of 10 mg vericiguat less often and received other substance classes of guideline-recommended therapy (GDMT) less frequently. The proportion of patients receiving four pillars of GDMT increased from 29% before vericiguat initiation to 44% afterwards. Conclusion In a real-world setting, despite higher age than in clinical trials, adherence and persistence of vericiguat appeared satisfactory across age categories. Initiation of vericiguat was associated with intensification of concomitant GDMT. Nevertheless, barriers to vericiguat up-titration and implementation of other GDMT, applying in particular to women and elderly patients, need to be investigated further.

A priority in preventive cardiology is to reduce the number of recurrent events and to prolong survival in patients with established coronary heart disease (CHD). Aim of the present study was to examine risk factors for long- term mortality in CHD patients who entered routine secondary prevention after a coronary event or intervention. Such patients, from the EUROASPIRE (EUROpean Action on Secondary Prevention through Intervention to Reduce Events) I and II studies in the region of Münster, Germany, were followed over a mean period of 8.0 years up to the end of 2005. Patients were up to 70 years of age at baseline when they were interviewed and examined using standardised methods. Baseline examination was carried out at least 6 months and at a mean of 19.5 months after the coronary event or procedure. In 367 patients from EUROASPIRE I and 380 patients from EUROASPIRE ü, a total of 125 deaths (16.7%) occurred during follow-up. Multivariate analyses, using Cox proportional hazards models, established diabetes mellitus and smoking as predictors for all-cause mortality with estimated hazard rate ratios (HRRs) of 2.24 (95% confidence interval (CI): 1.43-3.49) and 1.95 (95% CI: 1.23-3.10), respectively. Significant associations were found between diabetes mellitus and cardiovascular (HRR 2.36; 95% CI: 1.31-4.24) as well as CHD mortality (HRR 2.40; 95% CI: 1.25-4.59). Systolic blood pressure was significantly associated with increased cerebrovascular disease mortality ( HRR 1.04; 95% CI: 1.01-1.08 for 1 mmHg increase). In conclusion, long-term mortality in coronary patients from routine secondary prevention is substantial. Diabetes mellitus and smoking represent key issues in patients with established CHD.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels comprise a family of cation channels activated by hyperpolarized membrane potentials and stimulated by intracellular cyclic nucleotides. The four members of this family, HCN1–4, show distinct biophysical properties which are most evident in the kinetics of activation and deactivation, the sensitivity towards cyclic nucleotides and the modulation by tyrosine phosphorylation. The four isoforms are differentially expressed in various excitable tissues. This review will mainly focus on recent insights into the functional role of the channels apart from their classic role as pacemakers. The importance of HCN channels in the cardiac ventricle and ventricular hypertrophy will be discussed. In addition, their functional significance in the peripheral nervous system and nociception will be examined. The data, which are mainly derived from studies using transgenic mice, suggest that HCN channels contribute significantly to cellular excitability in these tissues. Remarkably, the impact of the channels is clearly more pronounced in pathophysiological states including ventricular hypertrophy as well as neural inflammation and neuropathy suggesting that HCN channels may constitute promising drug targets in the treatment of these conditions. This perspective as well as the current therapeutic use of HCN blockers will also be addressed.

Body weight regulation is a complex phenotype also depending on the action of uncoupling proteins (UCPs) that mediate the \"uncoupling\" of respiration leading to the dissipation of energy as heat. This study investigated whether genetic variants in the genes encoding UCP-1 and UCP-3 are associated with different obesity-related phenotypes in 162 whites with a wide range of body mass index. All subjects were genotyped for the polymorphisms UCP-1 A-3826G, UCP-1 Ala64Thr, and UCP-3 C-55T using a PCR-based restriction method with appropriate enzymes. The frequencies of the UCP-1 3826G, UCP-1 64Thr, and UCP-3 55T alleles were 27.2%, 12.0%, and 22.8%, respectively. No significant associations were observed between polymorphism and body mass index or obesity. However, after adjustment for gender, age, body mass index, and diabetes mellitus the waist-to-hip ratio was significantly associated with UCP-1 Ala64Thr ( P=0.003) and UCP-3 C-55T ( P=0.02) but not with UCP-1 A-3826G. The higher waist-to-hip ratios associated with the UCP-1 64Thr and UCP-3 55T alleles were due to higher waist circumference in these allele carriers. In conclusion, central obesity in whites as reflected by an increased waist-to-hip ratio is associated with the UCP-1 Ala64Thr and UCP-3 C-55T polymorphisms. To what extent these genotypes contribute to the overall cardiovascular risk remains to be elucidated.