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AbstractBackground:The natural course of macrovascular events in patients with type 2 diabetes was analyzed: what are the risk factors, and what is the relationship to the use of self-monitoring of blood glucose (SMBG)?Methods:Data were retrieved from ROSSO—a German retrospective observational study—which followed 3,268 patients from diagnosis of type 2 diabetes for 6.5 ± 1.6 years. We compared patients with or without a nonfatal macrovascular event (myocardial infarction or stroke) and patients using or not using SMBG.Results:At baseline, worse glycemic control and higher body mass index were not risk factors for macrovascular events. Moreover, there was no association with classic risk factors like blood pressure or total cholesterol. Overall, there was a higher incidence of stroke than of myocardial infarction (0.78% vs. 0.51%). Myocardial infarction was positively associated with male sex, and stroke with age (P< 0.001 for each). Patients using SMBG compared to patients not using SMBG had fewer myocardial infarctions (2.0% vs. 4.0%, P= 0.002) and strokes (3.6% vs. 5.7%, P= 0.005), experienced a stroke later after diagnosis of type 2 diabetes (5.1 ± 1.9 vs. 3.8 ± 2.1 years, P< 0.001), and had a higher mean hemoglobin A1c in the years before a myocardial infarction (7.8 ± 1.8% vs. 6.8 ± 1.1%, P= 0.003) or a stroke (8.0 ± 1.8% vs. 7.1 ± 1.2%, P= 0.003). However, classic cardiovascular risk factors did not differ between patients using or not using SMBG.Conclusions:In patients with type 2 diabetes SMBG was associated with a lower event rate of myocardial infarction (−50%) and stroke (−37%), although at baseline the classic risk factors for macrovascular events were not different in both groups. [ABSTRACT FROM AUTHOR]

The surprisingly low number of about 25,000 genes in the human genome [1] confirmed a fairly accurate estimate given by King and Jukes in 1969 based on population genetical arguments [2]. On the other hand, the number of different transcripts vastly exceeds gene number. This fact intensified the search for alternatively spliced genes. Recent results [1,3,4-7] suggest that more than 60% of the human genes are alternatively spliced, some of them with a myriad of different splice forms. Alternative splicing is found in all higher eukaryotic species in varying frequency. In this paper we focus on a particular form of alternative splicing, the so-called mutually exclusive exon usage (MEEU). In most known examples mutually exclusive exons are arranged in cassettes of highly similar exons suggesting that they have been derived by exon duplication [8-10]. Since classical gene-finding programs may fail to correctly predict such genes [11-16], we present a method, which is based on local similarity of exons, to detect gene candidates with mutually exclusive exon usage. We have screened the entire genome of D. melanogaster and found five new genes with MEEU in addition to eight previously described cases. Additional 1703 candidate regions of putative mutually exclusive exons were identified. [ABSTRACT FROM AUTHOR]

While several studies investigated the effects of mechanical or electrical stimulation on osseointegration and bone fracture healing, little is known about the molecular and cellular impact of combined biophysical stimulation on peri-implant osseointegration. Therefore, we established an in vitro system, capable of applying shear stress and electric fields simultaneously. Capacitively coupled electric fields were used for electrical stimulation, while roughened Ti6Al4V bodies conducted harmonically oscillating micromotions on collagen scaffolds seeded with human osteoblasts. Different variations of single and combined stimulation were applied for three days, while samples loaded with Ti6Al4V bodies and untreated samples served as control. Metabolic activity, expression of osteogenic markers and bone remodeling markers were investigated. While combined stimulation showed no substantial benefit compared to sole mechanical stimulation, we observed that 25 µm micromotions applied by roughened Ti6Al4V bodies led to a significant increase in gene expression of osteocalcin and tissue inhibitor of metalloprotease 1. Additionally, we found an increase in metabolic activity and expression of bone remodeling markers with reduced procollagen type 1 synthesis after 100 mVRMS electrical stimulation. We were able to trigger specific cellular behaviors using different biophysical stimuli. In future studies, different variations of electrical stimulation will be combined with interfacial micromotions. [ABSTRACT FROM AUTHOR]

Regenerative agriculture has been associated with improved soil structure and soil fertility. However, conclusive evidence of its efficacy has remained elusive owing to a lack of long-term experimental studies. In this study, we assessed the impact of diverse regenerative agricultural measures on soil mechanical and hydraulic properties and indicators. Tested treatment factors included reduced tillage versus plowing, along with different levels of compost, mulch, and the application of ferments and compost tea. We measured in situ soil strength via soil penetration (from 0 to 0.8 m depth) and shear resistance (at 0.08 and 0.23 m depth) and assessed field-saturated hydraulic conductivity and ex situ soil aggregate stability (at 0.07 and 0.23 m depth). The experiments were conducted at five sites in Hesse, Germany, including one organic long-term experiment (LTE, since 2010) in Neu-Eichenberg and three organic and one conventional on-farm experiments to cover different soil types, weather conditions, and field practices. The soil types are classified as Luvisol and Vertic Cambisols, and the soil texture ranges from silt loam to silty clay loam. In the LTE, significant differences in aggregate stability and shear resistance were noted between treatments, with a higher geometric mean aggregate diameter at 0.07 m depth in 2021 and 2022 and a higher shear resistance at 0.19 m and 0.23 m in 2020 and in 2021, respectively, in the reduced tillage systems. However, no significant differences were observed among treatments for field-saturated hydraulic conductivity, which was overall very high, showing that reduced tillage did not negatively influence saturated infiltration, albeit bulk density is higher than in the conventionally plowed system. The soil penetration resistance was generally higher for the reduced tillage treatments across depths of 0.0–0.30 m, albeit not statistically significant (p > 0.05). Significantly higher water-stable aggregates and geometric mean diameters were observed for regenerative agricultural treatments in three of the on-farm experiments at a depth of 0.07 m. The shear resistance was significantly higher in regenerative agriculture units in specific years and depths. Although the outcomes are encouraging, the variability of the effects of reduced tillage and organic amendments in affecting soil properties highlights the need for further long-term research including farm trials. This is essential to fully understand the effects of regenerative practices on soil physical quality. • We assessed soil physical properties under regenerative agricultural measures. • Measurements were conducted in long-term and farm experiments. • Reduced tillage resulted in higher shear resistance and aggregate stability in some years. • Field saturated hydraulic conductivity was not affected by any treatment. [ABSTRACT FROM AUTHOR]

Background: Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a rare and potentially life-threatening bleeding disorder of the fetus/newborn. Antibodies against human platelet antigen 1a (HPA-1a) are associated with the most frequent FNAIT cases. There are no approved therapies for FNAIT prevention or treatment. RLYB211 is a polyclonal HPA-1a hyperimmune IgG being developed to prevent FNAIT., Objectives: To investigate whether a single dose of anti-HPA-1a (1000 IU) could markedly accelerate the elimination of HPA-1ab platelets transfused into healthy, HPA-1a-negative participants as compared with placebo., Methods: This randomized, single-blind, placebo-controlled, single-center, phase 1/2 proof-of-concept study (EudraCT: 2019-003459-12) included HPA-1a- and HLA-A2-negative healthy men. Cohort 1 received intravenous RLYB211 or placebo 1 hour after transfusion of HPA-1ab platelets. Cohort 1B received RLYB211 or placebo, followed by platelet transfusion 1 week later. Primary endpoint was the half-life of transfused platelets in circulation after administration of RLYB211 or placebo, determined by flow cytometry. Proof of concept was ≥90% reduction of half-life relative to placebo., Results: Twelve participants were allocated to cohort 1 or 1B and randomized to receive RLYB211 (n = 9) or placebo (n = 3). RLYB211 markedly accelerated the elimination of HPA-1ab platelets in all participants vs placebo. In cohort 1B, this effect was observed 7 days after RLYB211 administration. Two treatment-emergent adverse events were possibly related to treatment, both in RLYB211-treated participants. No participants developed HPA-1a antibodies at 12 or 24 weeks., Conclusion: These data support the hypothesis that anti-HPA-1a could be used as prophylaxis in women at risk of having an FNAIT-affected pregnancy., Competing Interests: Declaration of competing interests M.Kj., B.S., and J.KK. are stockholders of Prophylix AS, a Norwegian biotech company, which produced the study drug. M.Kj. and J.KK. are currently consultants for Rallybio, which is the sponsor of the study. R.A. and Z.B. are employees of Rallybio. J.KK. also provides consultancy services for ROS Therapeutics, Glycorex Transplantation AB, and Johnson & Johnson. German Red Cross Blood Donor Service Baden-Württemberg-Hessen gGmbH has a contract with Rallybio for the present study. The remaining authors declare no competing financial interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: This study was to compare the outcomes of 360° intra-operative laser retinopexy (ILR) and focal laser retinopexy in treating patients with pars plans vitrectomy (PPV) for primary rhegmatogenous retinal detachment (RRD). To identify other potential risk factors for retinal re-detachment after primary PPV., Methods: This was a retrospective cohort study. Three hundred and forty-four consecutive cases of primary rhegmatogenous retinal detachment treated with PPV were included between July 2013 and July 2018. Clinical characteristics and surgical outcomes were compared between focal laser retinopexy and additional 360° intra-operative laser retinopexy groups. Both univariate and multiple variable analysis were used to identify potential risk factors for retinal re-detachment., Results: Median follow-up was 6.2 months (Q1, Q3:2.0, 17.2). As estimated with survival analysis, the 360º ILR group had the incidence of 9.74% and focal laser 19.54% at 6 months postoperatively. At 12 months postoperatively the difference was 10.78% vs. 25.21%. The difference in survival rates was significant (p = 0.0021). In multivariate Cox regression, the risk factors for retinal re-detachment were without additional 360° ILR, diabetes and macula off before the primary surgery (relatively OR = 0.456, 95%-CI [0.245-0.848], p < 0.05; OR = 2.301, 95% CI [1.130-4.687], p < 0.05; OR = 2.243, 95% CI [1.212-4.149], p < 0.05)., Conclusion: Additional 360° ILR group had a significantly lower rate of retinal re-detachment when compared with focal laser retinopexy group. Our study also elucidated that diabetes and macular off before the primary surgery might also be the potential risk factors for higher rate of retinal re-detachment outcome., Trial Registration: This was a retrospective cohort study., (© 2023. The Author(s).)

Natural products from fungi, especially Ascomycota, play a major role in therapy and drug discovery. Fungal strains originating from marine habitats offer a new avenue for finding unusual molecular skeletons. Here, the marine-derived fungus Epicoccum nigrum (strain 749) was found to produce the azaphilonoid compounds acetosellin and 5',6'-dihydroxyacetosellin. The latter is a new natural product. The biosynthesis of these polyketide-type compounds is intriguing, since two polyketide chains are assembled to the final product. Here we performed 13 C labeling studies on solid cultures to prove this hypothesis for acetosellin biosynthesis., Competing Interests: Conflict of Interest: The authors declare no conflict of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: The incidence of type 2 diabetes is increasing disproportionately in individuals <65 years of age. It is not known whether disease characteristics in these younger patients are similar to "classic" late-onset type 2 diabetes., Methods: In the epidemiological cohort study entitled "Retrolective Study: Self-Monitoring of Blood Glucose and Outcome in Patients with Type 2 Diabetes," a total of 3268 patients from randomly contacted primary care practices were documented during a mean follow-up period of 6.5 years. All newly diagnosed patients of these practices were included., Results: At diagnosis, 64.2% of the patients were aged < or =65 years. Thereof, 57.2% were male, whereas in the age group >65 years only 35.0% were male (p < 0.001). The younger group exhibited more severe metabolic deterioration at diagnosis and in the following years than the older group. Conversely, the older group presented at diagnosis with a higher prevalence of cardiovascular risk factors. Self-monitoring of blood glucose (SMBG) was more prominent in the younger group. In both age groups, the use of SMBG was associated with a significantly lower risk (p = 0.003) of a combined end point (severe diabetic complication or all-cause mortality)., Conclusions: There are considerable differences in disease characteristics between people diagnosed with type 2 diabetes during 45-65 years of age versus diagnosis at a later age. Type 2 diabetes diagnosed before the age of 65 years disproportionately affected men and exhibited a more severe disease course, but was characterized by significantly less cardiovascular risk factors in comparison to type 2 diabetes diagnosed at a later age. The use of SMBG was associated with a better clinical outcome in both age groups.

The addition product of sodium hydride and the 2,3-dihydro-1,3-diborole (CiPr) 2 (BEt) 2 CHMe (3c) reacted with [{(C 5 Me 5 )FeCl} x ] to produce the green sandwich complex [(C 5 Me 5 )Fe{n 5 -(CiPr) 2 (BEt) 2 CMe}] (2 c), which formally contains 16 valence electrons (VE). Complex 2c has unexpected structural properties in the solid state: the 1,3-diborolyl ring is extremely folded (41°), and the Fe-C2 distance is short (1.90 Å). Analogously, violet Ru complexes 4a,c,d were obtained from 3a,c, NaH or tBuLi, and [{(C 5 Me 5 )RuCl} 4 ]. With the less bulky heterocycles 3 b,e the new 30 VE triple-decker complexes [(C 5 Me 5 )Ru{μ,n 5 -(CR 1 ) 2 (BR 2 ) 2 CMe}RuH(C 5 Me 5 )] (5b,e) were formed, which contain a Ru-H bond. Cyclic voltammetric studies revealed the existence of stable anions 2c - and 4d - formed by reversible one-electron reduction at -1.26 and -1.40 V, respectively (vs. SCE). The red-brown anions were further characterized by ESR spectroscopy following stepwise reduction of the neutral species with potassium in THF. Addition of CO to 4a and 4d led to formation of the monocarbonyl complexes [(C 5 Me 5 )Ru(CO){n 5 -(CR 1 ) 2 -(BR 2 ) 2 CMe}] (6a,d), and 6d was characterized by X-ray structure analysis. The heterocycle in 6d is less folded (19°) than in 2 c. Its CO ligand causes a 28.5° tilt of the cyclic ligands. Reaction of CO with 2 c yielded a red product of unknown structure. The electronic structure of 2 was studied by EH-MO theory, which revealed a unique bonding in the sandwich. The s̀ electron density of the B-C bonds participates in the bonding to the iron atom; this demonstrates that the number of bonding electrons is the same as in ferrocene. Thus, the complexes 2 actually have 18 VE., (Copyright © 1996 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)