Effective prevention is needed to combat the worldwide epidemic of type 2 diabetes. We investigated the long-term extent of beneficial effects of lifestyle intervention and metformin on diabetes ...prevention, originally shown during the 3-year Diabetes Prevention Program (DPP), and assessed whether these interventions reduced diabetes-associated microvascular complications.
The DPP (1996-2001) was a randomised trial comparing an intensive lifestyle intervention or masked metformin with placebo in a cohort selected to be at very high risk of developing diabetes. All participants were offered lifestyle training at the end of the DPP. 2776 (88%) of the surviving DPP cohort were followed up in the DPP Outcomes Study (DPPOS, Sept 1, 2002, to Jan 2, 2014) and analysed by intention to treat on the basis of their original DPP assignment. During DPPOS, the original lifestyle intervention group was offered lifestyle reinforcement semi-annually and the metformin group received unmasked metformin. The primary outcomes were the development of diabetes and the prevalence of microvascular disease. For the assessment of microvascular disease, we used an aggregate microvascular outcome, composed of nephropathy, retinopathy, and neuropathy.
During a mean follow-up of 15 years, diabetes incidence was reduced by 27% in the lifestyle intervention group (hazard ratio 0·73, 95% CI 0·65-0·83; p<0·0001) and by 18% in the metformin group (0·82, 0·72-0·93; p=0·001), compared with the placebo group, with declining between-group differences over time. At year 15, the cumulative incidences of diabetes were 55% in the lifestyle group, 56% in the metformin group, and 62% in the placebo group. The prevalences at the end of the study of the aggregate microvascular outcome were not significantly different between the treatment groups in the total cohort (placebo 12·4%, 95% CI 11·1-13·8; metformin 13·0%, 11·7-14·5; lifestyle intervention 11·3%, 10·1-12·7). However, in women (n=1887) the lifestyle intervention was associated with a lower prevalence (8·7%, 95% CI 7·4-10·2) than in the placebo (11·0%, 9·6-12·6) and metformin (11·2%, 9·7-12·9) groups, with reductions in the lifestyle intervention group of 21% (p=0·03) compared with placebo and 22% (p=0·02) compared with metformin. Compared with participants who developed diabetes, those who did not develop diabetes had a 28% lower prevalence of microvascular complications (relative risk 0·72, 95% CI 0·63-0·83; p<0·0001).
Lifestyle intervention or metformin significantly reduced diabetes development over 15 years. There were no overall differences in the aggregate microvascular outcome between treatment groups; however, those who did not develop diabetes had a lower prevalence of microvascular complications than those who did develop diabetes. This result supports the importance of diabetes prevention.
National Institute of Diabetes and Digestive and Kidney Diseases.
A novel role for IGF‐I in MSC chondrogenesis was determined. IGF‐I effects were evaluated in the presence or absence of TGF‐β signaling by conditionally inactivating the TGF‐β type II receptor. We ...found that IGF‐I had potent chondroinductive actions on MSCs. IGF‐I effects were independent from and additive to TGF‐β.
Introduction: Mesenchymal stem cells (MSCs) can be isolated from adult bone marrow (BM), expanded, and differentiated into several cell types, including chondrocytes. The role of IGF‐I in the chondrogenic potential of MSCs is poorly understood. TGF‐β induces MSC chondrogenic differentiation, although its actions are not well defined. The aim of our study was to define the biological role of IGF‐I on proliferation, chondrogenic condensation, apoptosis, and differentiation of MSCs into chondrocytes, alone or in combination with TGF‐β and in the presence or absence of TGF‐β signaling.
Materials and Methods: Mononuclear adherent stem cells were isolated from mouse BM. Chondrogenic differentiation was induced by culturing high‐density MSC pellets in serum‐ and insulin‐free defined medium up to 7 days, with or without IGF‐I and/or TGF‐β. We measured thymidine incorporation and stained 2‐day‐old pellets with TUNEL, cleaved caspase‐3, peanut‐agglutinin, and N‐cadherin. Seven‐day‐old pellets were measured in size, stained for proteoglycan synthesis, and analyzed for the expression of collagen II and Sox‐9 by quantitative real time PCR. We obtained MSCs from mice in which green fluorescent protein (GFP) was under the Collagen2 promoter and determined GFP expression by confocal microscopy. We conditionally inactivated the TGF‐β type II receptor (TβRII) in MSCs using a cre‐lox system, generating TβRII knockout MSCs (RIIKO‐MSCs).
Results and Conclusions: IGF‐I modulated MSC chondrogenesis by stimulating proliferation, regulating cell apoptosis, and inducing expression of chondrocyte markers. IGF‐I chondroinductive actions were equally potent to TGF‐β1, and the two growth factors had additive effects. Using RIIKO‐MSCs, we showed that IGF‐I chondrogenic actions are independent from the TGF‐β signaling. We found that the extracellular signal‐related kinase 1/2 mitogen‐activated protein kinase (Erk1/2 MAPK) pathway mediated the TGF‐β1 mitogenic response and in part the IGF‐I proliferative action. Our data, by showing the role of IGF‐I and TGF‐β1 in the critical steps of MSC chondrogenesis, provide critical information to optimize the therapeutic use of MSCs in cartilage disorders.
Abstract
Background
We studied risk factors, antibodies, and symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a diverse, ambulatory population.
Methods
A ...prospective cohort (n = 831) previously undiagnosed with SARS-CoV-2 infection underwent serial testing (SARS-CoV-2 polymerase chain reaction, immunoglobulin G IgG) for 6 months.
Results
Ninety-three participants (11.2%) tested SARS-CoV-2-positive: 14 (15.1%) asymptomatic, 24 (25.8%) severely symptomatic. Healthcare workers (n = 548) were more likely to become infected (14.2% vs 5.3%; adjusted odds ratio, 2.1; 95% confidence interval, 1.4–3.3) and severely symptomatic (29.5% vs 6.7%). IgG antibodies were detected after 79% of asymptomatic infections, 89% with mild-moderate symptoms, and 96% with severe symptoms. IgG trajectories after asymptomatic infections (slow increases) differed from symptomatic infections (early peaks within 2 months). Most participants (92%) had persistent IgG responses (median 171 days). In multivariable models, IgG titers were positively associated with symptom severity, certain comorbidities, and hospital work. Dyspnea and neurologic changes (including altered smell/taste) lasted ≥ 120 days in ≥ 10% of affected participants. Prolonged symptoms (frequently more severe) corresponded to higher antibody levels.
Conclusions
In a prospective, ethnically diverse cohort, symptom severity correlated with the magnitude and trajectory of IgG production. Symptoms frequently persisted for many months after infection.
Clinical Trials Registration. NCT04336215.
In a diverse, ambulatory cohort (548 healthcare workers; 283 nonhealthcare workers), 11.2% tested positive for SARS-CoV-2 over 6-month follow-up. COVID-19 symptom severity correlated with magnitude and trajectory of IgG production. Symptoms lasting ≥ 30 days afflicted one-third of infected participants.
Gut ausbalanciert: Eine Serie von Dibenzobicyclo3,2,2nonanen wurde entwickelt, die als „Konformationswaagen“ zur Untersuchung von schwachen Wechselwirkungen wie der π‐Wasserstoffbrücke OH⋅⋅⋅π(Ar) ...(siehe Schema, rot O) sowie von Wechselwirkungen zwischen Lösungsmittel und gelöstem Stoff dienen. Die Modellverbindungen können genutzt werden, um die Auswirkungen des Austauschs einer OH‐Gruppe gegen ein Fluoratom zu untersuchen oder die Arenaffinität von Schwefel‐ mit der von Sauerstoffzentren zu vergleichen.
Although the genetic defect underlying achondroplasia has been known for over a decade, no effective therapies to stimulate bone growth have emerged. Here we review the recent literature and ...summarize the molecular mechanisms underlying disease pathology and examine their potential as therapeutic targets. Currently used preclinical models are discussed in the context of recent advances with a special focus on C-type natriuretic peptide.
Research on the mutation in Fibroblast Growth Factor Receptor 3 (FGFR3) that causes achondroplasia suggests that disease results from increased signal transduction from the mutant receptor. Thus, current therapeutic strategies have focused on reducing signals emanating from FGFR3. First-generation therapies directly targeting FGFR3, such as kinase inhibitors and neutralizing antibodies, designed for targeting FGFR3 in cancer, are still in the preclinical phase and have yet to translate into the management of achondroplasia. Counteracting signal transduction pathways downstream of FGFR3 holds promise with the discovery that administration of C-type natriuretic peptide to achondroplastic mice ameliorates their clinical phenotype. However, more research into long-term effectiveness and safety of this strategy is needed. Direct targeting of therapeutic agents to growth plate cartilage may enhance efficacy and minimize side effects of these and future therapies.
Current research into the pathogenesis of achondroplasia has expanded our understanding of the mechanisms of FGFR3-induced disease and has increased the number of approaches that we may use to potentially correct it. Further research is needed to validate these approaches in preclinical models of achondroplasia.
Co-crystal screening is routinely undertaken using high-throughput solution growth. We report a low- to medium-throughput approach, encompassing both a melt and solution crystallization step as a ...route to the identification of co-crystals. Prior to solution studies, a melt growth step was included utilizing the Kofler mixed fusion method. This method allowed elucidation of the thermodynamic landscape within the binary phase diagram and was found to increase overall screening efficiency. The pharmaceutically acceptable adduct nicotinamide was selected and screened against a small set of active pharmaceutical ingredients (APIs) (ibuprofen (both the racemic compound (R/S) and S-enantiomer), fenbufen, flurbiprofen (R/S), ketoprofen (R/S), paracetamol, piracetam, and salicylic acid) as part of a larger systematic study of synthon stability. From the screen, three new co-crystal systems have been identified (ibuprofen (R/S and S) and salicylic acid) and their crystal structures determined. Because of poor crystal growth synchrotron radiation was required for structure solution of the S-ibuprofen nicotinamide co-crystal. Two further potential systems have also been discovered (fenbufen and flurbiprofen), but crystals suitable for structure determination have yet to be obtained. A greater ability to control crystallization kinetics is required to yield phase-pure single-crystalline material for full verification of this crystal engineering strategy.
Cover crop–based organic rotational no-till soybean production has attracted attention from farmers, researchers, and other agricultural professionals because of the ability of this new system to ...enhance soil conservation, reduce labor requirements, and decrease diesel fuel use compared to traditional organic production. This system is based on the use of cereal rye cover crops that are mechanically terminated with a roller-crimper to create in situ mulch that suppresses weeds and promotes soybean growth. In this paper, we report experiments that were conducted over the past decade in the eastern region of the United States on cover crop–based organic rotational no-till soybean production, and we outline current management strategies and future research needs. Our research has focused on maximizing cereal rye spring ground cover and biomass because of the crucial role this cover crop plays in weed suppression. Soil fertility and cereal rye sowing and termination timing affect biomass production, and these factors can be manipulated to achieve levels greater than 8,000 kg ha−1, a threshold identified for consistent suppression of annual weeds. Manipulating cereal rye seeding rate and seeding method also influences ground cover and weed suppression. In general, weed suppression is species-specific, with early emerging summer annual weeds (e.g., common ragweed), high weed seed bank densities (e.g. > 10,000 seeds m−2), and perennial weeds (e.g., yellow nutsedge) posing the greatest challenges. Due to the challenges with maximizing cereal rye weed suppression potential, we have also found high-residue cultivation to significantly improve weed control. In addition to cover crop and weed management, we have made progress with planting equipment and planting density for establishing soybean into a thick cover crop residue. Our current and future research will focus on integrated multitactic weed management, cultivar selection, insect pest suppression, and nitrogen management as part of a systems approach to advancing this new production system. Nomenclature: Common ragweed, Ambrosia artemisiifolia L.; yellow nutsedge, Cyperus esculentus L.; cereal rye, Secale cereale L.; corn, Zea mays L.; soybean, Glycine max (L). Merr.; wheat, Triticum aestivum L. La producción orgánica de soya en sistemas de rotación con cero labranza basados en cultivos de cobertura, ha atraído la atención de productores, investigadores y otros profesionales agrícolas por la habilidad de este nuevo sistema de mejorar la conservación del suelo, reducir los requerimientos de mano de obra y disminuir el uso de combustible diesel en comparación con la producción orgánica tradicional. Este sistema está basado en el uso de centeno como cultivo de cobertura el cual es terminado mecánicamente con un rodillo de cuchillas para crear una cobertura de residuos in situ que suprime malezas y promueve el crecimiento de la soya. En este artículo, reportamos experimentos que fueron realizados durante la década pasada en la región este de los Estados Unidos sobre la producción orgánica de soya en sistemas de rotación con cero labranza basados en cultivos de cobertura, y delineamos las estrategias actuales de manejo y las necesidades futuras de investigación. Nuestra investigación se ha enfocado en maximizar la cobertura y la biomasa del centeno de primavera debido al papel crucial que este cultivo de cobertura juega en la supresión de malezas. La fertilidad del suelo y el momento de siembra y término del centeno afectan la producción de biomasa, y estos factores pueden ser manipulados para alcanzar niveles mayores a 8,000 kg ha−1, el cual es el umbral identificado para la supresión consistente de malezas anuales. Manipular la densidad y métodos de siembra también influencia la cobertura del suelo y la supresión de malezas. En general, la supresión de malezas es específica a la especie, siendo las malezas anuales de verano que emergen temprano (e.g. Ambrosia artemisiifolia), los banco de semillas con altas densidades (e.g. >10,000 semillas m−2), y las malezas perennes (e.g. Cyperus esculentus) los mayores retos. Debido a los retos de maximizar el potencial de supresión de malezas del centeno, hemos encontrado que el cultivar con altos residuos también puede mejorar el control de malezas significativamente. Adicionalmente al cultivo de cobertura y el manejo de malezas, hemos progresado con el equipo y la densidad de siembra para el establecimiento de la soya en capas gruesas de residuos de cultivos de cobertura. Nuestra investigación actual y futura se centrará en el manejo integrado de malezas multitáctico, la selección de cultivares, la supresión de plagas insectiles, y el manejo del nitrógeno como parte de un enfoque de sistemas para el avance de este nuevo sistema de producción.
Radical‐cation salts of BEDT‐TTF with chiral anions provide the opportunity to combine chirality with conductivity in the same molecular material. We report here two salts, ...(BEDT‐TTF)3NaAl(C2O4)3·nitromethane and (BEDT‐TTF)3(NH4)0.83Cr1.17(C2O4)3·nitromethane. The former crystallises in space group P21 and the latter in P212121. The use of nitromethane alone as the electrolyte for electrocrystallisation produces no crystals, but the addition of chiral (R)‐(–)‐carvone yields crystals of these two new chiral radical‐cation salts of BEDT‐TTF through chiral induction from racemic tris(oxalato)aluminate(III) and tris(oxalato)chromate starting materials. The honeycomb anion layers in these salts contain a single enantiomer of tris(oxalato)metallate and creates hexagonal cavities that are smaller than those found in the superconducting β″ salts in this tris(oxalate)metallate family, which gives preference for smaller solvents to be included, such as nitromethane. The chromium salt has a non‐stoichiometric composition of the anion layer, which provides an electron doping effect to the donor layer.
The use of a chiral electrolyte has produced two new chiral radical‐cation salts of BEDT‐TTF from racemic ammonium tris(oxalato)aluminate(III) and ‐chromate. One of the salts has a non‐stoichiometric composition of 0.11 electrons per molecule doped to the band‐insulating donor layer.
...the publication of an essential diagnostics list (EDL) for priority settings by WHO in 2018 has been a key step in recognising the importance of diagnostics. ...the COVID-19 pandemic has greatly ...raised awareness of the crucial importance of diagnostics. ...a 2019 study suggested that India has only 1151 accredited medical laboratories, whereas the USA, with a quarter of India's population, has 260 000 accredited medical laboratories. Because low political prioritisation is the key cause of poor access to diagnostics, we explore how we can use the framework of Shiffman and Smith to achieve political change. Because technology is an enabler of many of the putative solutions in this Commission, we discuss the crucial role of technological innovation and also propose solutions via changes in policy, governance, and finance, and in infrastructure, workforce, and quality.
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