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Stress-regulated Arabidopsis GAT2 is a low affinity γ-aminobutyric acid (GABA) transporter.
No full textThe four carbon non-proteinogenic amino acid γ-aminobutyric acid (GABA) accumulates to high levels in plants in response to various abiotic and biotic stress stimuli, and plays a role in C:N balance, signaling and as a transport regulator. Expression in Xenopus oocytes and voltage-clamping allowed characterizing Arabidopsis GAT2 (At5g41800) as low affinity GABA transporter with a K0.5GABA~8 mM. L-alanine and butylamine represented additional substrates. GABA-induced currents were strongly dependent on the membrane potential, reaching highest affinity and highest transport rates at strongly negative membrane potentials. Mutation of Ser17, previously reported to be phosphorylated in planta, did not result in altered affinity. In short term stress experiment, AtGAT2 mRNA levels were upregulated at low water potential and under osmotic stress (polyethylene glycol, mannitol). Furthermore, AtGAT2 promoter activity was detected in vascular tissues, in maturating pollen, and the phloem unloading region of young seeds. Even though this suggested a role of AtGAT2 in long distance transport and loading of sink organs, under the conditions tested neither AtGAT2 overexpressing plants nor atgat2 or atgat1 T-DNA insertion lines, or atgat1 atgat2 double knockout mutants differed from wild type plants in growth on GABA, in amino acid levels or resistance to salt and osmotic stress
Panel stacking is a threat to consensus statement validity.
No full textConsensus statements can be very influential in medicine and public health. Some of these statements use systematic evidence synthesis but others fail on this front. Many consensus statements use panels of experts to deduce perceived consensus through Delphi processes. We argue that stacking of panel members towards one particular position or narrative is a major threat, especially in absence of systematic evidence review. Stacking may involve financial conflicts of interest, but non-financial conflicts of strong advocacy can also cause major bias. Given their emerging importance, we describe here how such consensus statements may be misleading, by analysing in depth a recent high-impact Delphi consensus statement on COVID-19 recommendations as a case example. We demonstrate that many of the selected panel members and at least 35% of the core panel members had advocated towards COVID-19 elimination (zero-COVID) during the pandemic and were leading members of aggressive advocacy groups. These advocacy conflicts were not declared in the Delphi consensus publication, with rare exceptions. Therefore, we propose that consensus statements should always require rigorous evidence synthesis and maximal transparency on potential biases towards advocacy or lobbyist groups to be valid. While advocacy can have many important functions, its biased impact on consensus panels should be carefully avoided
Impact of Small Aortic Annuli on the Performance of Transcatheter Aortic Valve Replacement Bioprostheses: An Updated Meta-analysis of Recent Studies.
No full textA metanalysis of available randomized controlled trials and observational studies comparing self-expanding and balloon-expandable bioprostheses in patients with small aortic annulus and aortic stenosis for short and midterm hemodynamic and clinical outcomes was performed. 21 studies with a total 8647 patients (self-expanding, n=4,336 patients vs balloon-expandable, n= 4,311 patients) were included. Self-expanding bioprostheses had a lower post-operative mean gradient at 30 days (MD -5.16, 95%CI 4.7-5.5, p value <0.001) and at one year (MD -6.6, 95%CI 6.1-7.03, p value <0.001), with a larger indexed Effective Orifice Area (0.17, 95%CI 0.13-0.22, p value <0.001and 0.17, 95%CI 0.08-0.27, p value < 0.001) at both time intervals. Balloon-expandable bioprostheses had a higher risk of 30-day and 1-year severe prosthesis-patient mismatch (RR 1.07, 95%CI 1.04-1.09, p value < 0.001; RR 1.07, 95%CI 1.04-1.11, p value <0.001). 30-day and 1 year paravalvular leaks (RR 0.99, 95%CI 0.98-0.99, p value < 0.001; RR 0.89, 95%CI 0.82-0.95, p value <0.001) and permanent pacemaker implantation (RR 0.97, 95%CI .94-0.99, p value 0.01, I2= 40%,) were lower in balloon-expandable group. Balloon-expandable bioprostheses were associated with lower risk of in-hospital stroke (RR 0.99, 95%CI 0.98-1,p value= 0.01). In conclusion, in patients with small aortic annulus and aortic stenosis, SE bioprostheses have superior haemodynamic performance but higher rates of PVL, PPI and in-hospital stroke. BE bioprostheses were associated with a higher risk of severe PPM
Depression and anxiety symptoms are underestimated risk factors for postoperative prognosis in patients with Type 2 diabetes and peripheral artery disease undergoing partial foot amputation: Results from a prospective cohort study.
No full textOBJECTIVE
The aim of this study was to evaluate the prevalence and impact of depression and anxiety symptoms on post-operative prognosis and 1-year all-cause mortality in a large unique cohort of patients with Type 2 diabetes (T2D) and peripheral artery disease (PAD) after partial foot amputation (PFA).
METHODS
Prospective cohort study with 1-year follow-up of 785 consecutive patients (mean age 60.9 ± 9.1 years; 64.1% males) with T2D and PAD after PFA. Depressive symptoms were assessed by Patient Health Questionnaire-9 (PHQ-9) and anxiety symptoms by Hamilton Anxiety Rating Scale (HARS). We used multivariable Cox proportional hazard models to examine the association of depression and anxiety with all-cause mortality.
RESULTS
One-year all-cause mortality was 16.9% (n = 133). 331 (42.1%) patients had PHQ-9 score ≥ 10 indicating major depressive disorder. After adjusting for confounders, PHQ-9 score ≥ 10 was associated with an increased risk of 1-year all-cause mortality (HR = 1.68 (95%CI[1.16-2.44], p = 0.006). Depression dimensions of negative self-feeling and suicidal ideations were independently associated with 1-year mortality (HR = 1.26 (95%CI[1.24-1.55], p = 0.029 and HR = 2.37 (95%CI[1.89-2.96], p 30) were associated with increased 1-year mortality (HR = 2.25(95%CI [1.26-4.05], p = 0.006).
CONCLUSION
Depressive symptoms and severe anxiety have shown independently increased risk of 1-year all-cause mortality in patients with T2D and PAD requiring PFA. Our results indicate that screening for anxiety and depression should be considered under these circumstances to identify patients at increased risk to allow appropriate intervention
Stepwise dehydration of thomsonite (THO) with disordered Si/Al distribution: a new partially hydrated phase
Get PDFThe structural transformations occurring as a function of increasing temperature in zeolites are of interest because the porous structure, and therefore the physical properties, can significantly change.
Zeolites with THO framework type are small-pore materials, which received attention because of their applications in catalytic processes. The majority of THO zeolites (synthetic and natural) are characterized by an ordered distribution of the cations at the tetrahedral sites. To date, few cases of disordered thomsonite have been reported. In this study, we investigated the dehydration behavior of a natural thomsonite with disordered Si/Al distribution and chemical composition Ca3.34Na2.66Si11Al9O40∙12H2O. The structure was determined from room temperature (RT) to 698 K in order to compare the thermal behavior with that reported for the ordered variety. Accurate structural analysis was performed by in situ single crystal X-ray diffraction. The dehydration starts at 348 K. Up to 498 K, thomsonite gradually releases four H2O. From 498 to 573 K, additional four H2O are lost and the space group changes from orthorhombic (Pbmn) to monoclinic (P21/n). This partially hydrated phase is characterized by a unit-cell volume contraction of -3% with respect to the RT phase and by a rearrangement of the extraframework cations in the zeolitic pores. The thermally treated thomsonite is able to reabsorb 50% of the lost H2O and transform to the orthorhombic phase, equivalent to that observed at lower temperatures. However, the diffraction pattern analysis indicated a high degree of mosaicity, most probably due to the residual stress accumulated during the phase transformation
Practical solutions for including Sex As a Biological Variable (SABV) in preclinical neuropsychopharmacological research.
No full textRecently, many funding agencies have released guidelines on the importance of considering sex as a biological variable (SABV) as an experimental factor, aiming to address sex differences and avoid possible sex biases to enhance the reproducibility and translational relevance of preclinical research. In neuroscience and pharmacology, the female sex is often omitted from experimental designs, with researchers generalizing male-driven outcomes to both sexes, risking a biased or limited understanding of disease mechanisms and thus potentially ineffective therapeutics. Herein, we describe key methodological aspects that should be considered when sex is factored into in vitro and in vivo experiments and provide practical knowledge for researchers to incorporate SABV into preclinical research. Both age and sex significantly influence biological and behavioral processes due to critical changes at different timepoints of development for males and females and due to hormonal fluctuations across the rodent lifespan. We show that including both sexes does not require larger sample sizes, and even if sex is included as an independent variable in the study design, a moderate increase in sample size is sufficient. Moreover, the importance of tracking hormone levels in both sexes and the differentiation between sex differences and sex-related strategy in behaviors are explained. Finally, the lack of robust data on how biological sex influences the pharmacokinetic (PK), pharmacodynamic (PD), or toxicological effects of various preclinically administered drugs to animals due to the exclusion of female animals is discussed, and methodological strategies to enhance the rigor and translational relevance of preclinical research are proposed
Ueber Interglazialfloren und Interglazialklimate, mit besonderer Berücksichtigung der Pflanzenreste von Gondiswil-Zell und Pianico-Sellere
No full textERS/EBMT clinical practice guideline on treatment of pulmonary chronic graft-versus-host disease in adults.
No full textChronic graft-versus-host disease (cGvHD) is a common complication after allogeneic haematopoietic stem cell transplantation, characterised by a broad disease spectrum that can affect virtually any organ. Although pulmonary cGvHD is a less common manifestation, it is of great concern due to its severity and poor prognosis. Optimal management of patients with pulmonary cGvHD is complicated and no standardised approach is available.The purpose of this joint European Respiratory Society and European Society for Blood and Marrow Transplantation Task Force was to develop evidence-based recommendations regarding the treatment of pulmonary cGvHD phenotype bronchiolitis obliterans syndrome in adults. A multidisciplinary group representing specialists in haematology, respiratory medicine, methodology as well as patient advocates formulated eight PICO (Patient, Intervention, Comparison, Outcome) and two narrative questions. Following the ERS standardised methodology, we conducted systematic reviews to address these questions and used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to develop recommendations.The resulting guideline addresses common therapeutic options (inhalation therapy, fluticasone-azithromycin-montelukast, imatinib, ibrutinib, ruxolitinib, belumosudil, extracorporeal photopheresis and lung transplantation), as well as other aspects of general management, such as lung functional and radiological follow-up and pulmonary rehabilitation, for adults with pulmonary cGvHD phenotype bronchiolitis obliterans syndrome. These recommendations include important advancements that could be incorporated in the management of adults with pulmonary cGvHD, primarily aimed at improving and standardising treatment and improving outcomes
Availability of drugs and resistance testing for BPaLM regimen for rifampicin-resistant tuberculosis in Europe.
No full textOBJECTIVES
Multidrug-resistant/Rifampicin-resistant tuberculosis (TB) is a major obstacle to successful TB control. The recommendation by the World Health Organization to use bedaquiline, pretomanid, linezolid and moxifloxacin (BPaL(M)) for 6 months, based on results of three trials with high efficacy and low toxicity, has revolutionized treatment options.
METHODS
In this study, representatives of the Tuberculosis Network European Trialsgroup (TBnet) in 44/54 countries of the WHO Europe region document the availability of the medicines and drug susceptibility testing (DST) of the BPaL(M) regimen through a structured questionnaire between September to November 2023.
RESULTS
24/44 (54.5%), 42/44 (95.5%), 43/44 (97.7%), and 43/44 (97.7%) had access to pretomanid, bedaquiline, linezolid, and moxifloxacin, respectively. Overall, 23/44 (52.3%) had access to all the drugs composing the BPaL(M) regimen. 7/44 (15.9%), 28/44 (63.6%), 34/44 (77.3%) and 36/44 (81.8%) had access to DST for pretomanid, bedaquiline, linezolid and moxifloxacin, respectively. DST was available for all medicines composing the BPaL(M) regimen in 6/44 (13.6%) countries.
CONCLUSION
Only in about half of the countries participating in the survey clinicians have access to all the BPaL(M) regimen drugs. In less than a fifth of countries, a complete DST is possible. Rapid scale up of DST capacity to prevent unnoticed spread of drug resistance and equal access to new regimens are urgently needed in Europe
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