The evening complex integrates photoperiod signals to control flowering in rice.

Plants use photoperiodism to activate flowering in response to a particular daylength. In rice, flowering is accelerated in short-day conditions, and even a brief exposure to light during the dark period (night-break) is sufficient to delay flowering. Although many of the genes involved in controlling flowering in rice have been uncovered, how the long- and short-day flowering pathways are integrated, and the mechanism of photoperiod perception is not understood. While many of the signaling components controlling photoperiod-activated flowering are conserved between Arabidopsis and rice, flowering in these two systems is activated by opposite photoperiods. Here we establish that photoperiodism in rice is controlled by the evening complex (EC). We show that mutants in the EC genes LUX ARRYTHMO (LUX) and EARLY FLOWERING3 (ELF3) paralogs abolish rice flowering. We also show that the EC directly binds and suppresses the expression of flowering repressors, including PRR37 and Ghd7. We further demonstrate that light acts via phyB to cause a rapid and sustained posttranslational modification of ELF3-1. Our results suggest a mechanism by which the EC is able to control both long- and short-day flowering pathways.

Assessment of combined α-GAL enzyme activity and lyso-GL3 for Fabry disease screening in women with chronic kidney disease.

INTRODUCTION: The spectrum of clinical presentation of Fabry disease (FD) in women is broad and challenging. The aim is to evaluate the effectiveness of an alternative screening method for FD in women. METHODS: A collaborative multicenter cross-sectional study to evaluate the sensitivity and specificity of the combination of two tests (α-GAL enzyme activity assay and lyso-GL3 assay) for the diagnosis of FD in women. We included women with chronic kidney disease (CKD) stages 3 to 5, receiving conservative treatment or on dialysis programs, from different nephrology services in Brazil. RESULTS: We evaluated 1874 patients that underwent blood collection for α-GAL and lyso-GL3 assays. Isolated decreased α-GAL enzyme activity was found in 64 patients (3.5%), while isolated increased lyso-GL3 levels were found in 67 patients (3.6%), with one patient presenting alterations in both tests. All cases with low α-GAL enzyme activity and/or increased lyso-GL3 levels underwent genetic analysis for FD variants (132 performed GLA genetic test). Low α-GAL enzyme activity had higher sensitivity and specificity to detect FD compared to the other measures (elevated lyso-GL3 alone or both altered). The negative predictive value (NPV) of α-GAL activity was 99%, and the positive predictive value (PPV) was 9.2%. For lyso-GL3 assay, the specificity was 99.7% and the PPV was 2.9%, therefore considered inferior to α-GAL assay. Both assays altered, had higher PPV (100%) and higher NPV (99.7%) considered the best method. We found 7 cases of GLA gene variants found, resulting in an initial prevalence of 0.37% for FD in this sample female population. CONCLUSION: This study contributes to the diagnostic value of the biomarkers α-GAL and lyso-GL3 in the context of FD in women with CKD. The combination of these biomarkers was an effective approach for the diagnosis of the disease, with high PPV and NPV.

Regional Disparities in Kidney Transplant Allocation in Brazil: A Retrospective Cohort Study.

BACKGROUND: Brazil has a large public transplant program, but it remains unclear if the kidney waitlist criteria effectively allocate organs. This study aimed to investigate whether gender, ethnicity, clinical characteristics, and Brazilian regions affect the chance of deceased donor kidney transplant (DDKT). METHODS: We conducted a retrospective cohort study using the National Transplant System/Brazil database, which included all patients on the kidney transplant waitlist from January 2012 to December 2022, followed until May 2023. The primary outcome assessed was the chance of DDKT, measured using subdistribution hazard and cause-specific hazard models (subdistribution hazard ratio [sHR]). RESULTS: We analyzed 118 617 waitlisted patients over a 10-year study period. Male patients had an sHR of 1.07 ([95% CI: 1.05-1.10], p < 0.001), indicating a higher chance of DDTK. Patients of mixed race and Yellow/Indigenous ethnicity had lower rates of receiving a transplant compared to Caucasian patients, with sHR of 0.97 (95% CI: 0.95-1) and 0.89 (95% CI: 0.95-1), respectively. Patients from the South region had the highest chance of DDKT, followed by those from the Midwest and Northeast, compared to patients from the Southeast, with sHR of 2.53 (95% CI: 2.47-2.61), 1.21 (95% CI: 1.16-1.27), and 1.10 (95% CI: 1.07-1.13), respectively. The North region had the lowest chance of DDTK, sHR of 0.29 (95% CI: 0.27-0.31). CONCLUSION: We found that women and racial minorities faced disadvantages in kidney transplantation. Additionally, we observed regional disparities, with the North region having the lowest chance of DDKT and longer times on dialysis before being waitlisted. In contrast, patients in the South regions had a chance of DDKT and shorter times on dialysis before being waitlisted. It is urgent to implement approaches to enhance transplant capacity in the North region and address race and gender disparities in transplantation.

Trends in inpatient burden from pressure injuries in the United States: Cross-sectional study National Inpatient Sample 2009-2019.

Pressure injuries are a significant comorbidity and lead to increased overall healthcare costs. Several European and global studies have assessed the burden of pressure injuries; however, no comprehensive analysis has been completed in the United States. In this study, we investigated the trends in the burden of pressure injuries among hospitalised adults in the United States from 2009 to 2019, stratified by sociodemographic subgroups. The length of admission, total cost of hospitalisation, and sociodemographic data was extracted from the National Inpatient Sample provided by the Healthcare Cost and Utilisation Project, Agency for Healthcare Research and Quality. Overall, the annual prevalence of pressure injuries and annual mean hospitalisation cost increased ($69,499.29 to $102,939.14), while annual mean length of stay decreased (11.14-9.90 days). Among all races, minority groups had higher average cost and length of hospitalisation. Our findings suggest that while the length of hospitalisation is decreasing, hospital costs and prevalence are rising. In addition, differing trends among racial groups exist with decreasing prevalence in White patients. Further studies and targeted interventions are needed to address these differences, as well as discrepancies in racial groups.

Adopting the International Consensus on ANA Patterns (ICAP) classification for reporting: the experience of Italian clinical laboratories.

The indirect immunofluorescence assay on HEp-2 cells (HEp-2 IFA) is still considered the reference method to detect anti-nuclear antibodies (ANA) because of its high sensitivity and represents a relevant tool for the diagnosis of autoimmune rheumatic diseases. During the last decade, the International Consensus on ANA Patterns (ICAP) initiative promoted harmonization and understanding of HEp-2 IFA staining pattern nomenclature, as well as promoting their use in patient care by providing interpretation for HEp-2 IFA test results. In conjunction with a nationwide survey on the evolution of autoantibody diagnostics in autoimmune rheumatic diseases, we focused on the adherence of the Italian laboratories to the ICAP nomenclature analyzing its lights and shadows. The recent ICAP-oriented report, largely used today among Italian laboratories, also represents a further step in harmonizing and improving communication with the clinicians, adding value to laboratory findings and helping with critical clinical decisions.

Luminescent Properties of ß-(hydroxyaryl)-butenolides and Fluorescence Quenching in Water.

This work describes the luminescent properties of the new compound ß-(hydroxyaryl)-butenolides recently discovered. The compounds were subjected to UV-Vis absorption and fluorescence analyzes when diluted in different solvents. Through the results, it was possible to observe that the ß-hydroxyarylutenolides have two absorption bands, one at 289-291 nm and the other with higher intensity at 328-354 nm. The emission band between 385-422 nm is observed under excitation at 324-327 nm. The compounds showed solvatochromism as a function of the analyzed solvent. In water, fluorescence quenching of all compounds occurs. Therefore, studies with compound containing the methylenedioxy group attached in phenyl ring were carried at different concentrations of water in DMSO. The decrease in the fluorescence intensity of this compound is linearly proportional to the increase in the amount of water in the DMSO, with a minimum detection volume of 0.028%. Quantum yields of three compounds were evaluated in different solvents, showing that the relationship between the structure of the compound and the solvent is essential for a high value. The fluorescence quantum yield was also measured by Thermal Lens Spectroscopy (TLS) using DMSO as the solvent, confirming the high value for the analyzed samples. Despite being preliminary, the studies revealed that these compounds have luminescent properties that could be applied in the development of chemical sensors for detecting water in DMSO.

Treatment of Brachioradial Pruritus: A Tertiary Center Retrospective Analysis.

This retrospective study investigates the efficacy of 2 treatment regimens, pregabalin alone versus pregabalin combined with ketamine, amitriptyline, and lidocaine cream, in reducing itch in patients with brachioradial pruritus at a tertiary care center. Electronic medical records of 64 brachioradial pruritus patients seen at the University of Miami Itch Center were analyzed. A significant reduction in itch scores was seen with both treatments, with no significant difference between the groups. A small number of patients experienced adverse effects, including drowsiness and weight gain with pregabalin and skin irritation with ketamine, amitriptyline, and lidocaine cream. Ultimately, our findings underscore the potential of utilizing combined therapy for difficult-to-treat brachioradial pruritus cases and implementing individualized approaches for managing neuropathic pruritus. Further controlled clinical trials are needed to establish optimal treatment protocols.

Application of natural language processing to predict final recommendation of Brazilian health technology assessment reports.

INTRODUCTION: Health technology assessment (HTA) plays a vital role in healthcare decision-making globally, necessitating the identification of key factors impacting evaluation outcomes due to the significant workload faced by HTA agencies. OBJECTIVES: The aim of this study was to predict the approval status of evaluations conducted by the Brazilian Committee for Health Technology Incorporation (CONITEC) using natural language processing (NLP). METHODS: Data encompassing CONITEC's official report summaries from 2012 to 2022. Textual data was tokenized for NLP analysis. Least Absolute Shrinkage and Selection Operator, logistic regression, support vector machine, random forest, neural network, and extreme gradient boosting (XGBoost), were evaluated for accuracy, area under the receiver operating characteristic curve (ROC AUC) score, precision, and recall. Cluster analysis using the k-modes algorithm categorized entries into two clusters (approved, rejected). RESULTS: The neural network model exhibited the highest accuracy metrics (precision at 0.815, accuracy at 0.769, ROC AUC at 0.871, and recall at 0.746), followed by XGBoost model. The lexical analysis uncovered linguistic markers, like references to international HTA agencies' experiences and government as demandant, potentially influencing CONITEC's decisions. Cluster and XGBoost analyses emphasized that approved evaluations mainly concerned drug assessments, often government-initiated, while non-approved ones frequently evaluated drugs, with the industry as the requester. CONCLUSIONS: NLP model can predict health technology incorporation outcomes, opening avenues for future research using HTA reports from other agencies. This model has the potential to enhance HTA system efficiency by offering initial insights and decision-making criteria, thereby benefiting healthcare experts.

"Untargeting" autoantibodies using genome editing, a proof-of-concept study.

Autoantibodies (AAbs) are useful biomarkers and many have direct pathogenic role. Current standard therapies for elimination of specific B/plasma-cell clones are not fully efficient. We apply CRISPR/Cas9 genome-editing to knockout V(D)J rearrangements that produce pathogenic AAbs in vitro. HEK293T cell-lines were established stably expressing a humanized anti-dsDNA Ab (clone 3H9) and a human-derived anti-nAChR-α1 Ab (clone B12L). For each clone, five CRISPR/Cas9 heavy-chain's CDR2/3-targeting guided-RNAs (T-gRNAs) were designed. Non-Target-gRNA (NT-gRNA) was control. After editing, levels of secreted Abs were evaluated, as well as 3H9 anti-dsDNA and B12L anti-AChR reactivities. T-gRNAs editing decreased expression of heavy-chain genes to ∼50-60%, compared to >90% in NT-gRNA, although secreted Abs levels and reactivity to their respective antigens in T-gRNAs decreased ∼90% and âˆ¼ 95% compared with NT-gRNA for 3H9 and B12L, respectively. Sequencing indicated indels at Cas9 cut-site, which could lead to codon jam, and consequently, knockout. Additionally, remaining secreted 3H9-Abs presented variable dsDNA reactivity among the five T-gRNA, suggesting the exact Cas9 cut-site and indels further interfere with antibody-antigen interaction. CRISPR/Cas9 genome-editing was very effective to knockout the Heavy-Chain-IgG genes, considerably affecting AAbs secretion and binding capacity, fostering application of this concept to in vivo models as a potential novel therapeutic approach for AAb-mediated diseases.

Combined 13-valent pneumococcal conjugate and 23-valent pneumococcal polysaccharide vaccine regimens for adults with systemic lupus erythematosus: Does the sequence of pneumococcal vaccination affect immunogenicity responses? A single-center cohort study in Brazil.

OBJECTIVE: A combination of 13-valent pneumococcal conjugate vaccine (PCV13) and 23-valent pneumococcal polysaccharide vaccine (PPSV23) is currently recommended for adults with systemic lupus erythematosus (SLE). However, data on the immunogenicity elicited by sequential pneumococcal vaccination in this patient population are scarce. In this study, we compared short-term antibody responses to both PCV13/PPSV23 (≥8-week interval) and PPSV23/PCV13 (≥12-month interval) vaccination strategies in pneumococcal vaccine-naive adults with SLE. METHODS: This longitudinal, open-label, quasi-randomized study was performed in a single-center cohort of adults (18 years or older) with SLE. In both vaccination groups, blood samples were collected immediately before administering the first dose of the pneumococcal vaccine (timepoint T0), 4-6 weeks after the priming dose (T1), and 4-6 weeks after the booster dose (T2). We focused on the 12 shared serotypes between PCV13 and PPSV23, and compared the following immunogenicity outcomes between the groups at T2: anti-pneumococcal antibody geometric mean concentration (ApAb GMC), fold increase in ApAb levels (FI-ApAb), overall seroprotection rate, and overall seroconversion rate. The protective level for each pneumococcal serotype was set at 1.3 µg/mL. We used the multi-analyte immunodetection method to determine serum levels of ApAbs. RESULTS: Thirty-four patients with SLE were screened between April 2019 and January 2020, and 16 of them (mean age: 39.4 years, 87.5% female, and 100% on immunosuppressants) had evaluable immunogenicity results at T2. The median time elapsed between the pneumococcal vaccinations was 56 days in the PCV13/PPSV23 group (n = 11 patients) and 16 months in the PPSV23/PCV13 group (n = 5 patients). Priming with PCV13 (PCV13/PPSV23 group), as opposed to PPSV23 (PPSV23/PCV13 group), yielded significantly better results regarding FI-ApAb, overall seroconversion rate, and overall seroprotection rate 4-6 weeks after each pneumococcal vaccination. A trend toward augmented ApAb GMC in the patients who received the PCV13/PPSV23 sequence was also observed. No relevant safety issues were identified with sequential pneumococcal vaccination. CONCLUSION: The PCV13-priming PPSV23-boost strategy in adults with SLE induced greater antibody responses for most immunogenicity outcomes than those elicited by the PPSV23/PCV13 strategy.

Analytical aspects of the antinuclear antibody test by HEp-2 indirect immunofluorescence: EFLM report on an international survey.

OBJECTIVES: Detection of antinuclear antibodies (ANA) by indirect immunofluorescence assay using HEp-2 cells (HEp-2 IFA) is used to screen for various autoimmune diseases. HEp-2 IFA suffers from variability, which hampers harmonization. METHODS: A questionnaire was developed to collect information on HEp-2 IFA methodology, computer-assisted diagnosis (CAD) systems, training, inter-observer variability, quality assessment, reagent lot change control, and method verification. The questionnaire was distributed to laboratories by Sciensano (Belgium), national EASI groups (Italy, Croatia, Portugal, Estonia, Greece) and ICAP (worldwide). Answers were obtained by 414 laboratories. The results were analysed in the framework of the recent EFLM/EASI/ICAP ANA recommendations (companion paper). RESULTS: Laboratories used either HEp-2, HEp-2000, or HEp-20-10 cells and most laboratories (80%) applied the same screening dilution for children and adults. The conjugate used varied between laboratories [IgG-specific (in 57% of laboratories) vs. polyvalent]. Sixty-nine percent of CAD users reviewed the automatic nuclear pattern and 53% of CAD users did not fully exploit the fluorescence intensity for quality assurance. Internal quality control was performed by 96% of the laboratories, in 52% of the laboratories only with strongly positive samples. Interobserver variation was controlled by 79% of the laboratories. Limited lot-to-lot evaluation was performed by 68% of the laboratories. Method verification was done by 80% of the respondents. CONCLUSIONS: Even though many laboratories embrace high-quality HEp-2 IFA, substantial differences in how HEp-2 IFA is performed and controlled remain. Acting according to the EFLM/EASI/ICAP ANA recommendations can improve the global performance and quality of HEp-2 IFA and nurture harmonization.

Detection of antinuclear antibodies: recommendations from EFLM, EASI and ICAP.

OBJECTIVES: Antinuclear antibodies (ANA) are important for the diagnosis of various autoimmune diseases. ANA are usually detected by indirect immunofluorescence assay (IFA) using HEp-2 cells (HEp-2 IFA). There are many variables influencing HEp-2 IFA results, such as subjective visual reading, serum screening dilution, substrate manufacturing, microscope components and conjugate. Newer developments on ANA testing that offer novel features adopted by some clinical laboratories include automated computer-assisted diagnosis (CAD) systems and solid phase assays (SPA). METHODS: A group of experts reviewed current literature and established recommendations on methodological aspects of ANA testing. This process was supported by a two round Delphi exercise. International expert groups that participated in this initiative included (i) the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group "Autoimmunity Testing"; (ii) the European Autoimmune Standardization Initiative (EASI); and (iii) the International Consensus on ANA Patterns (ICAP). RESULTS: In total, 35 recommendations/statements related to (i) ANA testing and reporting by HEp-2 IFA; (ii) HEp-2 IFA methodological aspects including substrate/conjugate selection and the application of CAD systems; (iii) quality assurance; (iv) HEp-2 IFA validation/verification approaches and (v) SPA were formulated. Globally, 95% of all submitted scores in the final Delphi round were above 6 (moderately agree, agree or strongly agree) and 85% above 7 (agree and strongly agree), indicating strong international support for the proposed recommendations. CONCLUSIONS: These recommendations are an important step to achieve high quality ANA testing.

A comprehensive model for assessing and classifying patients with thrombotic microangiopathy: the TMA-INSIGHT score.

BACKGROUND: Thrombotic Microangiopathy (TMA) is a syndrome characterized by the presence of anemia, thrombocytopenia and organ damage and has multiple etiologies. The primary aim is to develop an algorithm to classify TMA (TMA-INSIGHT score). METHODS: This was a single-center retrospective cohort study including hospitalized patients with TMA at a single center. We included all consecutive patients diagnosed with TMA between 2012 and 2021. TMA was defined based on the presence of anemia (hemoglobin level < 10 g/dL) and thrombocytopenia (platelet count < 150,000/µL), signs of hemolysis, and organ damage. We classified patients in eight categories: infections; Malignant Hypertension; Transplant; Malignancy; Pregnancy; Thrombotic Thrombocytopenic Purpura (TTP); Shiga toxin-mediated hemolytic uremic syndrome (STEC-SHU) and Complement Mediated TMA (aHUS). We fitted a model to classify patients using clinical characteristics, biochemical exams, and mean arterial pressure at presentation. RESULTS: We retrospectively retrieved TMA phenotypes using automatic strategies in electronic health records in almost 10 years (n = 2407). Secondary TMA was found in 97.5% of the patients. Primary TMA was found in 2.47% of the patients (TTP and aHUS). The best model was LightGBM with accuracy of 0.979, and multiclass ROC-AUC of 0.966. The predictions had higher accuracy in most TMA classes, although the confidence was lower in aHUS and STEC-HUS cases. CONCLUSION: Secondary conditions were the most common etiologies of TMA. We retrieved comorbidities, associated conditions, and mean arterial pressure to fit a model to predict TMA and define TMA phenotypic characteristics. This is the first multiclass model to predict TMA including primary and secondary conditions.

IMPDH forms the cytoophidium in zebrafish.

Inosine monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step in de novo guanine nucleotide biosynthesis. Its activity is negatively regulated by the binding of GTP. IMPDH can form a membraneless subcellular structure termed the cytoophidium in response to certain changes in the metabolic status of the cell. The polymeric form of IMPDH, which is the subunit of the cytoophidium, has been shown to be more resistant to the inhibition by GTP at physiological concentrations, implying a functional correlation between cytoophidium formation and the upregulation of GTP biosynthesis. Herein we demonstrate that zebrafish IMPDH1b and IMPDH2 isoforms can assemble abundant cytoophidium in most of cultured cells under stimuli, while zebrafish IMPDH1a shows distinctive properties of forming the cytoophidium in different cell types. Point mutations that disrupt cytoophidium structure in mammalian models also prevent the aggregation of zebrafish IMPDHs. In addition, we discover the presence of the IMPDH cytoophidium in various tissues of larval and adult fish under normal growth conditions. Our results reveal that polymerization and cytoophidium assembly of IMPDH can be a regulatory machinery conserved among vertebrates, and with specific physiological purposes.

Development and validation of a simple web-based tool for early prediction of COVID-19-associated death in kidney transplant recipients.

This analysis, using data from the Brazilian kidney transplant (KT) COVID-19 study, seeks to develop a prediction score to assist in COVID-19 risk stratification in KT recipients. In this study, 1379 patients (35 sites) were enrolled, and a machine learning approach was used to fit models in a derivation cohort. A reduced Elastic Net model was selected, and the accuracy to predict the 28-day fatality after the COVID-19 diagnosis, assessed by the area under the ROC curve (AUC-ROC), was confirmed in a validation cohort. The better calibration values were used to build the applicable ImAgeS score. The 28-day fatality rate was 17% (n = 235), which was associated with increasing age, hypertension and cardiovascular disease, higher body mass index, dyspnea, and use of mycophenolate acid or azathioprine. Higher kidney graft function, longer time of symptoms until COVID-19 diagnosis, presence of anosmia or coryza, and use of mTOR inhibitor were associated with reduced risk of death. The coefficients of the best model were used to build the predictive score, which achieved an AUC-ROC of 0.767 (95% CI 0.698-0.834) in the validation cohort. In conclusion, the easily applicable predictive model could assist health care practitioners in identifying non-hospitalized kidney transplant patients that may require more intensive monitoring. Trial registration: ClinicalTrials.gov NCT04494776.

PHYTOCHROME-INTERACTING FACTORS: a promising tool to improve crop productivity.

Light is a key determinant for plant growth, development, and ultimately yield. Phytochromes, red/far-red photoreceptors, play an important role in plant architecture, stress tolerance, and productivity. In the model plant Arabidopsis, it has been shown that PHYTOCHROME-INTERACTING FACTORS (PIFs; bHLH transcription factors) act as central hubs in the integration of external stimuli to regulate plant development. Recent studies have unveiled the importance of PIFs in crops. They are involved in the modulation of plant architecture and productivity through the regulation of cell division and elongation in response to different environmental cues. These studies show that different PIFs have overlapping but also distinct functions in the regulation of plant growth. Therefore, understanding the molecular mechanisms by which PIFs regulate plant development is crucial to improve crop productivity under both optimal and adverse environmental conditions. In this review, we discuss current knowledge of PIFs acting as integrators of light and other signals in different crops, with particular focus on the role of PIFs in responding to different environmental conditions and how this can be used to improve crop productivity.

COVID-19 in Kidney Transplant Recipients With Diabetes Mellitus: A Propensity Score Matching Analysis.

Kidney transplant recipients present higher rates of pre-existing comorbidities, in particular diabetes mellitus (DM), hypertension, and cardiac disease. We aimed to verify the main risk factors related to DM that contribute to COVID-19 progression and mortality in a kidney transplant setting. From March to August 2020, we evaluated 300 kidney transplant recipients affected by COVID-19. We used propensity score matching (PSM) to estimate the impact of DM on COVID-19. After matching, all baseline characteristics were well balanced between those with and without DM (n = 100 in each group). Case fatality rate, the requirement of invasive mechanical ventilation (IMV), and acute kidney injury (AKI) were associated with previous fasting blood glucose, and C-reactive protein (CRP), and lactate dehydrogenase (LDH) levels on admission. These findings were similar in kidney transplant patients with and without DM. Glycemia on admission and estimated glomerular filtration rate (eGFR) either on admission or basal correlated to the need of IMV and development of AKI, respectively. Poor glycaemic control, eGFR, markers of inflammation (CRP) and tissue damage (LDH) were indicative of COVID-19 burden in kidney transplant recipients and may be useful tools for risk-stratifying this population, independently of the DM status, during the pandemic.

Temporal Reduction in COVID-19-Associated Fatality Among Kidney Transplant Recipients: The Brazilian COVID-19 Registry Cohort Study.

Data from the general population suggest that fatality rates declined during the course of the pandemic. This analysis, using data extracted from the Brazilian Kidney Transplant COVID-19 Registry, seeks to determine fatality rates over time since the index case on March 3rd, 2020. Data from hospitalized patients with RT-PCR positive SARS-CoV-2 infection from March to August 2020 (35 sites, 878 patients) were compared using trend tests according to quartiles (Q1: <72 days; Q2: 72-104 days; Q3: 105-140 days; Q4: >140 days after the index case). The 28-day fatality decreased from 29.5% (Q1) to 18.8% (Q4) (pfor-trend = 0.004). In multivariable analysis, patients diagnosed in Q4 showed a 35% reduced risk of death. The trend of reducing fatality was associated with a lower number of comorbidities (20.7-10.6%, p for-trend = 0.002), younger age (55-53 years, pfor-trend = 0.062), and better baseline renal function (43.6-47.7 ml/min/1.73 m2, pfor-trend = 0.060), and were confirmed by multivariable analysis. The proportion of patients presenting dyspnea (pfor-trend = 0.001) and hypoxemia (pfor-trend < 0.001) at diagnosis, and requiring intensive care was also found reduced (pfor-trend = 0.038). Despite possible confounding variables and time-dependent sampling differences, we conclude that COVID-19-associated fatality decreased over time. Differences in demographics, clinical presentation, and treatment options might be involved.

CTPS forms the cytoophidium in zebrafish.

Cytidine triphosphate synthase (CTPS) catalyzes the rate-limiting step of de novo CTP biosynthesis. An intracellular structure of CTPS, the cytoophidium, has been found in many organisms including prokaryotes and eukaryotes. Formation of the cytoophidium has been suggested to regulate the activity and stability of CTPS and may participate in certain physiological events. Herein, we demonstrate that both CTPS1a and CTPS1b in zebrafish are able to form the cytoophidium in cultured cells. A point mutation, H355A, abrogates cytoophidium assembly of zebrafish CTPS1a and CTPS1b. In addition, we show the presence of CTPS cytoophidia in multiple tissues of larval and adult fish under normal conditions, while treatment with a CTPS inhibitor 6-diazo-5-oxo-l-norleucine (DON) can induce more cytoophidia in some tissues. Our findings reveal that forming the CTPS cytoophidium is a natural phenomenon of zebrafish and provide valuable information for future research on the physiological importance of this intracellular structure in vertebrates.

Association between urinary sodium excretion and hard outcomes in non-dialysis chronic kidney disease patients.

BACKGROUND: Restriction of sodium intake is routinely recommended for patients with chronic kidney disease (CKD). Whether or not sodium intake is associated with the progression of CKD and mortality remains uncertain. We evaluated the association between urinary sodium excretion (as a surrogate for sodium intake) with the occurrence of renal failure and mortality in patients with non-dialytic CKD. METHODS: We conducted a retrospective study of patients followed at a CKD clinic care hospital from October 2006 to March 2017. Adult patients with non-dialytic CKD were included. Using a time-to-event analysis, we examined the association of urinary sodium excretion as a categorical variable (categorized as quintiles: 1st quintile: 0.54-2.51 g; 2nd quintile: 2.52-3.11 g, 3rd quintile: 3.12-3.97 g, 4th quintile: 3.98-5.24 g and 5th quintile: 5.26-13.80 g) and the outcomes of interest. The primary outcome was defined as progression to end-stage renal disease requiring any type of renal replacement therapy. The secondary outcome was mortality. RESULTS: Two hundred five patients were included in the study (mean follow up of 2.6 years) with a mean eGFR of 26 (19-41) ml/min/1.73m2. 37 patients (18%) required renal replacement therapy and 52 (25,3%) died. There was association between urinary sodium excretion and need for renal replacement therapy (adjusted HR 0.245; 95%CI 0.660-0.912). There was no association between urinary sodium excretion and mortality in adjusted models. CONCLUSION: Moderate sodium intake was associated with a lower risk of renal failure.