Stress-regulated Arabidopsis GAT2 is a low affinity γ-aminobutyric acid (GABA) transporter.

The 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

Impact of Small Aortic Annuli on the Performance of Transcatheter Aortic Valve Replacement Bioprostheses: An Updated Meta-analysis of Recent Studies.

A 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

Short-term association between air temperature and mortality in seven cities in Norway: A time series analysis.

BACKGROUND The association between ambient air temperature and mortality has not been assessed in Norway. This study aimed to quantify for seven Norwegian cities (Oslo, Bergen, Stavanger, Drammen, Fredrikstad, Trondheim and Tromsø) the non-accidental, cardiovascular and respiratory diseases mortality burden due to non-optimal ambient temperatures. METHODS We used a historical daily dataset (1996-2018) to perform city-specific analyses with a distributed lag non-linear model with 14 days of lag, and pooled results in a multivariate meta-regression. We calculated attributable deaths for heat and cold, defined as days with temperatures above and below the city-specific optimum temperature. We further divided temperatures into moderate and extreme using cut-offs at the 1st and 99th percentiles. RESULTS We observed that 5.3% (95% confidence interval (CI) 2.0-8.3) of the non-accidental related deaths, 11.8% (95% CI 6.4-16.4) of the cardiovascular and 5.9% (95% CI -4.0 to 14.3) of the respiratory were attributable to non-optimal temperatures. Notable variations were found between cities and subgroups stratified by sex and age. The mortality burden related to cold dominated in all three health outcomes (5.1%, 2.0-8.1, 11.4%, 6.0-15.4, and 5.1%, -5.5 to 13.8 respectively). Heat had a more pronounced effect on the burden of respiratory deaths (0.9%, 0.2-1.0). Extreme cold accounted for 0.2% of non-accidental deaths and 0.3% of cardiovascular and respiratory deaths, while extreme heat contributed to 0.2% of non-accidental and to 0.3% of respiratory deaths. CONCLUSIONS Most of the burden could be attributed to the contribution of moderate cold. This evidence has significant implications for enhancing public-health policies to better address health consequences in the Norwegian setting

Panel stacking is a threat to consensus statement validity.

Consensus 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

NT-proBNP in systemic right ventricles: a new cutoff level for risk stratification?

INTRODUCTION AND OBJECTIVES The role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in the risk prediction of patients with systemic right ventricles (sRV) is not well defined. The aim of this study was to analyze the prognostic value of NT-proBNP in patients with an sRV. METHODS The prognostic value of NT-proBNP was assessed in 98 patients from the SERVE trial. We used an adjusted Cox proportional hazards model, survival analysis, and c-statistics. The composite primary outcome was the occurrence of clinically relevant arrhythmia, heart failure, or death. Correlations between baseline NT-proBNP values and biventricular volumes and function were assessed by adjusted linear regression models. RESULTS The median age [interquartile range] at baseline was 39 [32-48] years and 32% were women. The median NT-proBNP was 238 [137-429] ng/L. Baseline NT-proBNP concentrations were significantly higher among the 20 (20%) patients developing the combined primary outcome compared with those who did not (816 [194-1094] vs 205 [122-357]; P = .003). In patients with NT-proBNP concentrations > 75th percentile (> 429 ng/L), we found an exponential increase in the sex- and age-adjusted hazard ratio for the primary outcome. The prognostic value of NT-proBNP was comparable to right ventricular ejection fraction and peak oxygen uptake on exercise testing (c-statistic: 0.71, 0.72 and 0.71, respectively). CONCLUSIONS In patients with sRVs, NT-proBNP concentrations correlate with sRV volumes and function and may serve as a simple tool for predicting adverse outcomes

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.

OBJECTIVE 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

Practical solutions for including Sex As a Biological Variable (SABV) in preclinical neuropsychopharmacological research.

Recently, 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

Ultrasound in bone fracture diagnosis - a comparative meta-analysis and systematic review.

AIM This meta-analysis evaluates the diagnostic accuracy of ultrasound (US) for bone fractures over the past 47 years, comparing it to established imaging standards. MATERIAL AND METHODS We adhered to PRISMA 2020 guidelines to search Medline, EMBASE, and the Cochrane Library using tailored search strategies. The primary outcome, US diagnostic performance, was analyzed across various subgroups including clinical relevance, patient age, and anatomical considerations. The QUADAS-2 tool was employed to assess study quality and minimize bias. RESULTS From 5,107 initially identified studies, 75 met the inclusion criteria, encompassing 7,769 participants and 3,575 diagnosed fractures. The majority of studies were prospective (79%) and compared US primarily with plain radiography (76%) and CT scans (19%). Of these, 61 studies were amenable to systematic analysis, revealing US to have a sensitivity and specificity of 91% (95% CI: 90%-92%) and 91.3% (95% CI: 90.5%-92.1%), respectively. Likelihood ratios were favorable, with a positive value of 9.955 and a negative value of 0.087, and an odds ratio of 132.67. The area under the curve stood at 0.9715, indicating high diagnostic accuracy despite significant heterogeneity (I²=81.3% for sensitivity, 89.3% for specificity). CONCLUSION The evidence supports US as a highly accurate diagnostic tool for bone fractures, rivalling standard imaging methods like CT and radiography. Its notable diagnostic efficacy, combined with advantages in reducing pain, wait times, and radiation exposure, advocates for its broader application. Further validation in large-scale, randomized trials is essential to integrate US more fully into clinical guidelines for fracture management

Anterior cruciate ligament repair using dynamic intraligamentary stabilization grants 88.5% survival at minimum follow-up of 5 years.

PURPOSE The aim of this study was to report on the revision rates and clinical outcomes following dynamic intraligamentary stabilization (DIS) at a minimum follow-up of 5 years and to investigate which preoperative or intraoperative characteristics could influence revision rates or clinical scores. METHODS The authors retrospectively assessed all 609 knees that underwent ACL repair using DIS at a single centre. At a minimum follow-up of 5 years, patients were assessed using the Lysholm, International Knee Documentation Committee (IKDC) and Tegner scores, as well as passive flexion and extension. RESULTS At a follow-up of 5.1 ± 0.3 years (range, 5-10), of the 609 patients, 428 patients were available for clinical assessment. Anterior tibial translation decreased from 9.7 ± 2.1 to 7.8 ± 1.9 mm, and side-to-side difference decreased from 4.3 ± 2.3 to 1.5 ± 1.8 mm. The postoperative Lysholm score was 96.9 ± 5.6, subjective IKDC was 95.6 ± 6.1 and Tegner scores ranged from 4 to 11, of which 51% of patients had a score of 7 or more. The estimated survival rate was 86% for the first half of the cohort and increased to 91% for the second half of the cohort. CONCLUSION At a minimum follow-up of 5 years following ACL repair using DIS, it was found that it grants satisfactory clinical outcomes and that surgeons should inform patients who have predispositions about the higher risk of revision. LEVEL OF EVIDENCE Level IV retrospective study