External validation of the RIETE and SOME scores for occult cancer in patients with venous thromboembolism: a multicentre cohort study.

INTRODUCTION: Venous thromboembolism (VTE) may be the first sign of an undiagnosed cancer. The RIETE and SOME scores aim to identify patients with acute VTE at high risk of occult cancer. In the present study, we evaluated the performance of both scores. METHODS: The scores were evaluated in a retrospective cohort from two centers. The area under the receiver-operating characteristics curve (AUC) evaluated the discriminatory performance. RESULTS: The RIETE score was applied to 815 patients with provoked and unprovoked VTE, of whom 56 (6.9%) were diagnosed with cancer. Of the 203 patients classified as high-risk, 18 were diagnosed with cancer, representing 32.1% (18/56) of the total cancer diagnoses. In the group of 612 low-risk patients, 67.9% of the cancer cases were diagnosed (38/56). Sensitivity, specificity, negative and positive predictive values, and AUC were 32%, 76%, 94%, 9%, and 0.430 (95% confidence interval [CI], 0.38‒0.47), respectively. The SOME score could be calculated in 418 patients with unprovoked VTE, of whom 33 (7.9%) were diagnosed with cancer. Of the 45 patients classified as high-risk, three were diagnosed with cancer, representing 9.1% (3/33) of the total cancer diagnoses. In the group of 373 low-risk patients, 90.9% of the cancer cases were diagnosed (30/33). Sensitivity, specificity, negative and positive predictive values, and AUC were 33%, 88%, 94%, 20%, and 0.351 (95% CI, 0.27‒0.43), respectively. CONCLUSIONS: The performance of both scores was poor. Our results highlight the need to develop new models to identify high-risk patients who may benefit from an extensive cancer screening strategy.

Novel pyrrole based CB2 agonists: New insights on CB2 receptor role in regulating neurotransmitters' tone.

The cannabinoid system is one of the most investigated neuromodulatory systems because of its involvement in multiple pathologies such as cancer, inflammation, and psychiatric diseases. Recently, the CB2 receptor has gained increased attention considering its crucial role in modulating neuroinflammation in several pathological conditions like neurodegenerative diseases. Here we describe the rational design of pyrrole-based analogues, which led to a potent and pharmacokinetically suitable CB2 full agonist particularly effective in improving cognitive functions in a scopolamine-induced amnesia murine model. Therefore, we extended our study by investigating the interconnection between CB2 activation and neurotransmission in this experimental paradigm. To this purpose, we performed a MALDI imaging analysis on mice brains, observing that the administration of our lead compound was able to revert the effect of scopolamine on different neurotransmitter tones, such as acetylcholine, serotonin, and GABA, shedding light on important networks not fully explored, so far.

Membrane Proteome-Wide Screening of Autoantibodies in CIDP Using Human Cell Microarray Technology.

BACKGROUND AND OBJECTIVES: Autoantibody discovery in complex autoimmune diseases is challenging. Diverse successful antigen identification strategies are available, but, so far, have often been unsuccessful, especially in the discovery of protein antigens in which conformational and post-translational modification are critical. Our study assesses the utility of a human membrane and secreted protein microarray technology to detect autoantibodies in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: A cell microarray consisting of human embryonic kidney-293 cells expressing >5,000 human proteins was used. First, a validation step was performed with 4 serum samples from patients with autoimmune nodopathy (AN) to assess the ability of this technology to detect circulating known autoantibodies. The ability of the cell microarray technology to discover novel IgG autoantibodies was assessed incubating the array with 8 CIDP serum samples. Identified autoantibodies were subsequently validated using cell-based assays (CBAs), ELISA, and/or tissue immunohistochemistry and analyzed in a cohort of CIDP and AN (n = 96) and control (n = 100) samples. RESULTS: Serum anti-contactin-1 and anti-neurofascin-155 were detected by the human cell microarray technology. Nine potentially relevant antigens were found in patients with CIDP without other detectable antibodies; confirmation was possible in six of them: ephrin type-A receptor 7 (EPHA7); potassium-transporting ATPase alpha chain 1 and subunit beta (ATP4A/4B); leukemia-inhibitory factor (LIF); and interferon lambda 1, 2, and 3 (IFNL1, IFNL2, IFNL3). Anti-ATP4A/4B and anti-EPHA7 antibodies were detected in patients and controls and considered unrelated to CIDP. Both anti-LIF and anti-IFNL antibodies were found in the same 2 patients and were not detected in any control. Both patients showed the same staining pattern against myelinating fibers of peripheral nerve tissue and of myelinating neuron-Schwann cell cocultures. Clinically relevant correlations could not be established for anti-LIF and anti-IFNL3 antibodies. DISCUSSION: Our work demonstrates the utility of human cell microarray technology to detect known and discover unknown autoantibodies in human serum samples. Despite potential CIDP-associated autoantibodies (anti-LIF and anti-IFNL3) being identified, their clinical and pathogenic relevance needs to be elucidated in bigger cohorts.

Pleiotropic effects of trisomy and pharmacologic modulation on structural, functional, molecular, and genetic systems in a Down syndrome mouse model.

Down syndrome (DS) is characterized by skeletal and brain structural malformations, cognitive impairment, altered hippocampal metabolite concentration and gene expression imbalance. These alterations were usually investigated separately, and the potential rescuing effects of green tea extracts enriched in epigallocatechin-3-gallate (GTE-EGCG) provided disparate results due to different experimental conditions. We overcame these limitations by conducting the first longitudinal controlled experiment evaluating genotype and GTE-EGCG prenatal chronic treatment effects before and after treatment discontinuation. Our findings revealed that the Ts65Dn mouse model reflected the pleiotropic nature of DS, exhibiting brachycephalic skull, ventriculomegaly, neurodevelopmental delay, hyperactivity, and impaired memory robustness with altered hippocampal metabolite concentration and gene expression. GTE-EGCG treatment modulated most systems simultaneously but did not rescue DS phenotypes. On the contrary, the treatment exacerbated trisomic phenotypes including body weight, tibia microarchitecture, neurodevelopment, adult cognition, and metabolite concentration, not supporting the therapeutic use of GTE-EGCG as a prenatal chronic treatment. Our results highlight the importance of longitudinal experiments assessing the co-modulation of multiple systems throughout development when characterizing preclinical models in complex disorders and evaluating the pleiotropic effects and general safety of pharmacological treatments.

Vaccination status and outcomes in critical COVID-19 patients.

OBJECTIVE: To analyze the clinical characteristics and outcomes of patients with COVID-19-related acute respiratory failure on the basis of their vaccination status at the time of ICU admission. METHODS: We conducted a retrospective observational study using a prospective database of patients admitted to the ICU of a university hospital in the city of Murcia, in Spain, between January 1, 2021 and September 1, 2022. Clinical, analytical, and sociodemographic data were collected and analyzed on the basis of patient vaccination status. We adjusted for confounding variables using propensity score matching and calculated adjusted ORs and 95% CIs. RESULTS: A total of 276 patients were included in the study. Of those, 8.3% were fully vaccinated, 12% were partially vaccinated, and 79.7% were unvaccinated. Although fully vaccinated patients had more comorbidities, partially vaccinated patients had higher disease severity. The proportion of patients with severe acute respiratory failure was higher in the unvaccinated group, followed by the partially vaccinated group. No significant differences were found among the different groups regarding complications, duration of ventilatory support, or length of ICU/hospital stay. In the sample selected by propensity score matching, the number of patients with severe complications and the in-hospital mortality rate were higher in unvaccinated patients, but the differences were not significant. CONCLUSIONS: This study failed to show a significant improvement in outcomes in critically ill COVID-19 patients vaccinated against SARS-CoV-2. However, the CIs were wide and the mortality point estimates favored patients who received at least one dose of COVID-19 vaccine.

Diagnostic and Prognostic Potential of Multiparametric Renal MRI in Kidney Transplant Patients.

BACKGROUND: Multiparametric MRI provides assessment of functional and structural parameters in kidney allografts. It offers a non-invasive alternative to the current reference standard of kidney biopsy. PURPOSE: To evaluate the diagnostic and prognostic utility of MRI parameters in the assessment of allograft function in the first 3-months post-transplantation. STUDY TYPE: Prospective. SUBJECTS: 32 transplant recipients (54 ± 17 years, 20 females), divided into two groups according to estimated glomerular filtration rate (eGFR) at 3-months post-transplantation: inferior graft function (IGF; eGFR<45 mL/min/1.73 m2 , n = 10) and superior graft function (SGF; eGFR ≥ 45 mL/min/1.73 m2 , n = 22). Further categorization was based on the need for hemodialysis (C1) and decrease in s-creatinine (C2) at 1-week post-transplantation: delayed-graft-function (DGF: n = 4 C1, n = 10 C2) and early graft-function (EGF: n = 28 C1, n = 22 C2). FIELD STRENGTH/SEQUENCE: 3-T, pseudo-continuous arterial spin labeling, T1-mapping, and diffusion-weighted imaging. ASSESSMENT: Multiparametric MRI was evaluated at 1-week in all patients and 3-months after transplantation in 28 patients. Renal blood flow (RBF), diffusion coefficients (ADC, ΔADC, D, ∆ $$ \Delta $$ D, D*, flowing fraction f), T1 and ∆ $$ \Delta $$ T1 were calculated in cortex and medulla. The diagnostic and prognostic value of these parameters, obtained at 3-months and 1-week post-transplantation, respectively, was evaluated in the cortex to discriminate between DGF and EGF, and between SGF and IGF. STATISTICAL TESTS: Logistic regression, receiver-operating-characteristics, area-under-the-curve (AUC), confidence intervals (CIs), analysis-of-variance, t-test, Wilcoxon-Mann-Whitney test, Fisher's exact test, Pearson's correlation. P-value<0.05 was considered significant. RESULTS: DGF patients exhibited significantly lower cortical RBF and f and higher D*. The diagnostic value of MRI for detecting DGF was excellent (AUC = 100%). Significant differences between patients with IGF and SGF were found in RBF, ∆T1 , and ∆D. Multiparametric MRI showed higher diagnostic (AUC = 95.32%; CI: 88%-100%) and prognostic (AUC = 97.47%, CI: 92%-100%) values for detecting IGF than eGFR (AUC = 89.50%, CI: 79%-100%). DATA CONCLUSION: Multiparametric MRI may show high diagnostic and prognostic value in transplanted patients, yielding better results compared to eGFR measurements. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1.

Clinical impact of preservation fluid contamination on kidney transplant patients.

BACKGROUND: Kidney transplantation is associated with a high risk of infectious complications due to immunosuppressive therapy. Although infections may be transmitted from donor to transplant recipient through contaminated preservation solution (PS), the clinical impact of this is not well-understood. METHODS: We retrospectively evaluated PS contamination rates in a series of 339 patients who underwent cadaveric renal transplant at our centre. All patients with a positive culture received targeted preemptive therapy (PET). RESULTS: Of the 339 PS samples, 136 (40.1%) were positive for a microorganism, mainly coagulase-negative staphylococci (CoNS; n = 89;60.5%), gram-negative bacilli (n = 31;21.1%), non-CoNS gram-positive cocci (n = 18;12.2%), and Candida spp (n = 2;1.4%). Of the 136 positive cases, 42 (30.9%) received PET (12.4% of the cohort). No cases of urinary tract infection, surgical site infection, or graft loss were observed. Overall, our findings indicate that PS contamination, mainly by saprophytic skin flora (CoNS) is common. Only 8% of patients required antibiotic or antifungal therapy. CONCLUSION: The infection transmission rate from donors to recipients was negligible (0%), perhaps due to the early initiation of a targeted PET after isolation of a recognized pathogen. More data from large, prospective studies are needed to confirm these findings.

Early in vivo detection of denervation-induced atrophy by luminescence transient nanothermometry.

Denervation induces skeletal muscle atrophy due to the loss of control and feedback with the nervous system. Unfortunately, muscle atrophy only becomes evident days after the denervation event when it could be irreversible. Alternative diagnosis tools for early detection of denervation-induced muscle atrophy are, thus, required. In this work, we demonstrate how the combination of transient thermometry, a technique already used for early diagnosis of tumors, and infrared-emitting nanothermometers makes possible the in vivo detection of the onset of muscle atrophy at short (<1 day) times after a denervation event. The physiological reasons behind these experimental results have been explored by performing three dimensional numerical simulations based on the Pennes' bioheat equation. It is concluded that the alterations in muscle thermal dynamics at the onset of muscle atrophy are consequence of the skin perfusion increment caused by the alteration of peripheral nervous autonomous system. This work demonstrates the potential of infrared luminescence thermometry for early detection of diseases of the nervous system opening the venue toward the development of new diagnosis tools.

Vaccination status and outcomes in critical COVID-19 patients / Situação vacinal e desfechos em pacientes com COVID-19 em estado crítico

ABSTRACT Objective: To analyze the clinical characteristics and outcomes of patients with COVID-19-related acute respiratory failure on the basis of their vaccination status at the time of ICU admission. Methods: We conducted a retrospective observational study using a prospective database of patients admitted to the ICU of a university hospital in the city of Murcia, in Spain, between January 1, 2021 and September 1, 2022. Clinical, analytical, and sociodemographic data were collected and analyzed on the basis of patient vaccination status. We adjusted for confounding variables using propensity score matching and calculated adjusted ORs and 95% CIs. Results: A total of 276 patients were included in the study. Of those, 8.3% were fully vaccinated, 12% were partially vaccinated, and 79.7% were unvaccinated. Although fully vaccinated patients had more comorbidities, partially vaccinated patients had higher disease severity. The proportion of patients with severe acute respiratory failure was higher in the unvaccinated group, followed by the partially vaccinated group. No significant differences were found among the different groups regarding complications, duration of ventilatory support, or length of ICU/hospital stay. In the sample selected by propensity score matching, the number of patients with severe complications and the in-hospital mortality rate were higher in unvaccinated patients, but the differences were not significant. Conclusions: This study failed to show a significant improvement in outcomes in critically ill COVID-19 patients vaccinated against SARS-CoV-2. However, the CIs were wide and the mortality point estimates favored patients who received at least one dose of COVID-19 vaccine.

RESUMO Objetivo: Analisar as características clínicas e desfechos de pacientes com insuficiência respiratória aguda por COVID-19 com base na situação vacinal no momento da admissão na UTI. Métodos: Estudo observacional retrospectivo com um banco de dados prospectivo de pacientes admitidos na UTI de um hospital universitário em Múrcia, na Espanha, entre 1º de janeiro de 2021 e 1º de setembro de 2022. Dados clínicos, analíticos e sociodemográficos foram coletados e analisados com base na situação vacinal dos pacientes. Por meio de pareamento por escore de propensão, foram realizados ajustes de modo a levar em conta as variáveis de confusão. Além disso, foram calculadas as OR ajustadas e IC95%. Resultados: Foram incluídos no estudo 276 pacientes. Destes, 8,3% apresentavam vacinação completa, 12% apresentavam vacinação incompleta e 79,7% não haviam sido vacinados. Embora os pacientes com vacinação completa apresentassem mais comorbidades, os com vacinação incompleta apresentavam doença mais grave. A proporção de pacientes com insuficiência respiratória aguda grave foi maior nos não vacinados, seguidos daqueles com vacinação incompleta. Não foram observadas diferenças significativas entre os diferentes grupos quanto a complicações, tempo de suporte ventilatório ou tempo de internação na UTI/hospital. Na amostra selecionada pelo pareamento por escore de propensão, o número de pacientes com complicações graves e a taxa de mortalidade hospitalar foram maiores em pacientes não vacinados, mas as diferenças não foram significativas. Conclusões: Este estudo não conseguiu demonstrar uma melhoria significativa dos desfechos em pacientes com COVID-19 em estado crítico e vacinados contra o SARS-CoV-2. No entanto, os IC foram amplos e as estimativas pontuais de mortalidade favoreceram os pacientes que receberam pelo menos uma dose de vacina contra a COVID-19.

Effectiveness and safety of non-invasive ventilation in the management of cardiogenic shock.

INTRODUCTION AND OBJECTIVES: Cardiogenic shock (CS) has long been considered a contraindication for the use of non-invasive ventilation (NIV). The main objective of this study was to analyze the effectiveness, measured as NIV success, in patients with respiratory failure due to CS. As secondary objective, we studied risk factors for NIV failure and compared the outcome of patients treated with NIV versus invasive mechanical ventilation (IMV). METHODS: Retrospective study on a prospective database, over a period of 25 years, of all consecutively patients admitted to an intensive care unit, with a diagnosis of CS and treated with NIV. A comparison was made between patients on NIV and patients on IMV using propensity score matching analysis. RESULTS: Three hundred patients were included, mean age 73.8 years, mean SAPS II 49. The main cause of CS was acute myocardial infarction (AMI): 164 (54.7%). NIV failure occurred in 153 (51%) cases. Independent factors for NIV failure included D/E stages of CS, AMI, NIV related complications, and being transferred from the ward. In the propensity analysis, hospital mortality (OR 1.69, 95% CI 1.09-2.63) and 1 year mortality (OR 1.61, 95% CI 1.04-2.51) was higher in IMV. Mortality was lower with NIV (vs. EIT-IMV) in C stage (10.1% vs. 32.9%; p<0.001) but did not differ in D stage or E stage. CONCLUSIONS: NIV seems to be relatively effective and safe in the treatment of early-stage CS.

The coexistence of diabetic retinopathy and diabetic nephropathy is associated with worse kidney outcomes.

Background: Up to 50-60% of patients with diabetes have non-diabetic kidney disease (NDKD) on kidney biopsy. Diabetic retinopathy (DR) is a microvascular complication of diabetes frequently associated with diabetic nephropathy (DN). The objective of the current study was to investigate the kidney outcomes and survival in patients with biopsy diagnoses of DN and NDKD according to the presence of DR. Methods: We conducted an observational, multicentre and retrospective study of the pathological findings of renal biopsies from 832 consecutive patients with diabetes from 2002 to 2014 from 18 nephrology departments. The association of DR with kidney replacement therapy (KRT) or survival was assessed by Kaplan-Meier and Cox regression analyses. Results: Of 832 patients with diabetes and renal biopsy, 768 had a retinal examination and 221/768 (22.6%) had DR. During a follow-up of 10 years, 288/760 (37.9%) patients with follow-up data needed KRT and 157/760 (20.7%) died. The incidence of KRT was higher among patients with DN (alone or with NDKD) and DR [103/175 (58.9%)] than among patients without DR [88/216 (40.7%), P < .0001]. The incidence of KRT was also higher among patients with only NDKD and DR than among those without DR [18/46 (39.1%) versus 79/331 (23.9%), P < .0001]. In multivariate analysis, DR or DN were independent risk factors for KRT {hazard ratio [HR] 2.48 [confidence interval (CI) 1.85-3.31], P < .001}. DN (with or without DR) was also identified as an independent risk factor for mortality [HR 1.81 (CI 1.26-2.62), P = .001]. Conclusions: DR is associated with a higher risk of progression to kidney failure in patients with histological DN and in patients with NDKD.

A deep learning image analysis method for renal perfusion estimation in pseudo-continuous arterial spin labelling MRI.

Accurate segmentation of renal tissues is an essential step for renal perfusion estimation and postoperative assessment of the allograft. Images are usually manually labeled, which is tedious and prone to human error. We present an image analysis method for the automatic estimation of renal perfusion based on perfusion magnetic resonance imaging. Specifically, non-contrasted pseudo-continuous arterial spin labeling (PCASL) images are used for kidney transplant evaluation and perfusion estimation, as a biomarker of the status of the allograft. The proposed method uses machine/deep learning tools for the segmentation and classification of renal cortical and medullary tissues and automates the estimation of perfusion values. Data from 16 transplant patients has been used for the experiments. The automatic analysis of differentiated tissues within the kidney, such as cortex and medulla, is performed by employing the time-intensity-curves of non-contrasted T1-weighted MRI series. Specifically, using the Dice similarity coefficient as a figure of merit, results above 93%, 92% and 82% are obtained for whole kidney, cortex, and medulla, respectively. Besides, estimated cortical and medullary perfusion values are considered to be within the acceptable ranges within clinical practice.

mRNA COVID-19 Vaccination Does Not Exacerbate Symptoms or Trigger Neural Antibody Responses in Multiple Sclerosis.

BACKGROUND AND OBJECTIVE: In people with multiple sclerosis (pwMS), concern for potential disease exacerbation or triggering of other autoimmune disorders contributes to vaccine hesitancy. We assessed the humoral and T-cell responses to SARS-CoV-2 after mRNA vaccination, changes in disease activity, and development of antibodies against central or peripheral nervous system antigens. METHODS: This was a prospective 1-year longitudinal observational study of pwMS and a control group of patients with other inflammatory neurologic disorders (OIND) who received an mRNA vaccine. Blood samples were obtained before the first dose (T1), 1 month after the first dose (T2), 1 month after the second dose (T3), and 6 (T4), 9 (T5), and 12 (T6) months after the first dose. Patients were assessed for the immune-specific response, annualized relapse rate (ARR), and antibodies to onconeuronal, neural surface, glial, ganglioside, and nodo-paranodal antigens. RESULTS: Among 454 patients studied, 390 had MS (22 adolescents) and 64 OIND; the mean (SD) age was 44 (14) years; 315 (69%) were female; and 392 (87%) were on disease-modifying therapies. Antibodies to the receptor-binding domain were detected in 367 (86%) patients at T3 and 276 (83%) at T4. After a third dose, only 13 (22%) of 60 seronegative patients seroconverted, and 255 (92%) remained seropositive at T6. Cellular responses were present in 381 (93%) patients at T3 and in 235 (91%) patients at T6 including all those receiving anti-CD20 therapies and in 79% of patients receiving fingolimod. At T3 (429 patients) or T6 (395 patients), none of the patients had developed CNS autoantibodies. Seven patients had neural antibodies that were already present before immunization (3 adult patients with MS had MOG-IgG, 2 with MG and 1 with MS had neuronal cell surface antibodies [unknown antigen], and 1 with MS had myelin antibody reactivity [unknown antigen]. Similarly, no antibodies against PNS antigens were identified at T3 (427 patients). ARR was lower in MS and not significantly different in patients with OIND. Although 182 (40%) patients developed SARS-CoV-2 infection, no cases of severe COVID-19 or serious adverse events occurred. DISCUSSION: In this study, mRNA COVID-19 vaccination was safe and did not exacerbate the autoimmune disease nor triggered neural autoantibodies or immune-mediated neurologic disorders. The outcome of patients who developed SARS-CoV-2 infection was favorable.

Optimization of the most widely used serological tests for a harmonized diagnosis of Toxoplasma gondii infection in domestic pigs.

The intake of Toxoplasma gondii tissue cysts through raw or undercooked pork meat is one of the main infection sources for humans. Thus, surveillance is recommended to control and prevent infection in domestic pigs. However, the lack of comparative studies hampers the updating of their performance and the comparison of seroprevalence data. Therefore, the aim of this study was to develop and validate three in-house tests and accomplish a comparative analysis of the most widely used serological tests employed in pigs. A panel of sera from pigs experimentally infected with either oocysts or tissue cysts from type II and III isolates (n = 158) was used to develop and validate a tachyzoite-based Western blot assay. Then, this technique was used as a reference to develop and preliminary validate a lyophilized tachyzoite-based enzyme-linked immunosorbent assay and an immunofluorescence antibody test. Next, a comparative study of the three in-house tests and three widely used commercial ELISAs (IDScreen®, PrioCHECK™ and Pigtype®) was accomplished with the abovementioned sera together with an additional serum panel of pigs experimentally infected with oocysts from the type II isolate (n = 44) and a panel of naturally infected pigs (n = 244). The results obtained by the majority of the tests were regarded as reference, and data analyses included TG-ROC calculations and agreement tests. Finally, the kinetics of anti-T. gondii IgGs from experimentally infected pigs was analyzed. Excellent sensitivity (Se) and specificity (Sp) values (≥ 93%) and moderate to near perfect agreement (k = 0.63-0.91) were observed using sera from experimental infections without requiring further readjustment, except for PrioCHECK (100% Se, 73% Sp). However, the Se of IDScreen® (87%) and TgSALUVET WB (71%) and the Sp of PrioCHECK (72%) were slightly or notably reduced when sera from naturally infected animals were analyzed, which also influenced the kappa values (k = 0.30-0.91). Cutoff readjustments increased the Se and Sp values to equal to or above 97% for all tests, except for TgSALUVET WB, which can be used as a reference for initial validation of tests, but it is not recommended for routine diagnosis. Seroconversion was recorded from two weeks post-infection by most of the tests, with significantly higher IgG levels in sera from pigs infected with the T. gondii type III vs. type II isolate. Again, differences regarding the test employed were observed. Differences in the diagnostic performance among tests evidenced the need to harmonize serological techniques to obtain comparable and reliable results.

Cannabidiol negatively modulates adenosine A2A receptor functioning in living cells.

OBJECTIVES: Cannabidiol (CBD) is a phytocannabinoid with great potential in clinical applications. The mechanism(s) of action of CBD require further investigation. Previous studies suggested that adenosine A2A receptors (A2ARs) could play a role in CBD-induced effects. Here, we evaluated the ability of CBD to modify the function of A2AR. METHODS: We used HEK-293T cells transfected with the cDNA encoding the human A2AR and Gαs protein, both modified to perform bioluminescence-based assays. We first assessed the effect of CBD on A2AR ligand binding using an A2AR NanoLuciferase sensor. Next, we evaluated whether CBD modified A2AR coupling to mini-Gαs proteins using the NanoBiT™ assay. Finally, we further assessed CBD effects on A2AR intrinsic activity by recording agonist-induced cAMP accumulation. RESULTS: CBD did not bind orthosterically to A2AR but reduced the coupling of A2AR to Gαs protein and the subsequent generation of cAMP. CONCLUSION: CBD negatively modulates A2AR functioning.

Food Insecurity and Chronic Kidney Disease: Considerations for Practitioners.

The coronavirus disease 2019 pandemic has exacerbated existing health disparities related to food security status. Emerging literature suggests individuals with Chronic Kidney Disease (CKD) who are also food insecure have a greater likelihood of disease progression compared to food secure individuals. However, the complex relationship between CKD and food insecurity (FI) is understudied relative to other chronic conditions. The purpose of this practical application article is to summarize the recent literature on the social-economic, nutritional, to care through which FI may negatively impact health outcomes in individuals with CKD. While several studies have reported on the cross-sectional prevalence of FI among persons with CKD, literature is lacking about the severity and duration of exposure to FI on CKD outcomes. Future research is needed to better understand how FI impairs CKD care, nutritional and structural barriers that impact disease prevention and disease progression, and effective strategies to support patients.

CPT1C is required for synaptic plasticity and oscillatory activity that supports motor, associative and non-associative learning.

Carnitine palmitoyltransferase 1c (CPT1C) is a neuron-specific protein widely distributed throughout the CNS and highly expressed in discrete brain areas including the hypothalamus, hippocampus, amygdala and different motor regions. Its deficiency has recently been shown to disrupt dendritic spine maturation and AMPA receptor synthesis and trafficking in the hippocampus, but its contribution to synaptic plasticity and cognitive learning and memory processes remains mostly unknown. Here, we aimed to explore the molecular, synaptic, neural network and behavioural role of CPT1C in cognition-related functions by using CPT1C knockout (KO) mice. CPT1C-deficient mice showed extensive learning and memory deficits. The CPT1C KO animals exhibited impaired motor and instrumental learning that seemed to be related, in part, to locomotor deficits and muscle weakness but not to mood alterations. In addition, CPT1C KO mice showed detrimental hippocampus-dependent spatial and habituation memory, most probably attributable to inefficient dendritic spine maturation, impairments in long-term plasticity at the CA3-CA1 synapse and aberrant cortical oscillatory activity. In conclusion, our results reveal that CPT1C is not only crucial for motor function, coordination and energy homeostasis, but also has a crucial role in the maintenance of learning and memory cognitive functions. KEY POINTS: CPT1C, a neuron-specific interactor protein involved in AMPA receptor synthesis and trafficking, was found to be highly expressed in the hippocampus, amygdala and various motor regions. CPT1C-deficient animals exhibited energy deficits and impaired locomotion, but no mood changes were found. CPT1C deficiency disrupts hippocampal dendritic spine maturation and long-term synaptic plasticity and reduces cortical γ oscillations. CPT1C was found to be crucial for motor, associative and non-associative learning and memory.

In Vivo Effectiveness of Several Antimicrobial Locks To Eradicate Intravascular Catheter Coagulase-Negative Staphylococci Biofilms.

Tunneled central venous catheter (TCVC) related infection remains a challenge in the care of hemodialysis patients. We aimed to determine the best antimicrobial lock therapy (ALT) to eradicate coagulase-negative staphylococci (CoNS) biofilms. We studied the colonization status of the catheter every 30 days by quantitative blood cultures (QBC) drawn through all catheter lumens. Those patients with a significant culture (i.e.,100 to 1,000 CFU/mL) of a CoNS were classified as patients with a high risk of developing catheter-related bloodstream infections (CRBSI). They were assigned to receive daptomycin, vancomycin, teicoplanin lock solution, or the standard of care (SoC) (i.e., heparin lock). The primary endpoint was to compare eradication ability (i.e., negative QBC for 30 days after ending ALT) rates between different locks and the SoC. A second objective was to analyze the correlation between ALT exposure and isolation of CoNS with antimicrobial resistance. Daptomycin lock was associated with a significant higher eradication success than with the SoC: 85% versus 30% (relative risk [RR] = 14, 95% confidence interval [CI] = 2.4 - 82.7); followed by teicoplanin locks with a 83.3% success (RR = 11.7; 95% CI = 2 - 70.2). We observed CoNs isolates with a higher teicoplanin MIC in patients with repeated teicoplanin locks exposure (coefficient = 0.3; 95% CI = 0.11 - 0.47). However, teicoplanin MICs decreased in patients treated with vancomycin locks (coefficient = -0.56; 95% CI = -0.85 - -0.02). Methicillin-resistance decreased with accumulative ALT (RR = 0.82; 95% CI = 0.69 - 0.98). In this study, daptomycin locks achieve the highest eradication rate of CoNS from hemodialysis catheters in vivo.

In vivo grading of lipids in fatty liver by near-infrared autofluorescence and reflectance.

The prevalence of nonalcoholic fatty liver (NAFLD) is rapidly increasing worldwide. When untreated, it may lead to complications such as liver cirrhosis or hepatocarcinoma. The diagnosis of NAFLD is usually obtained by ultrasonography, a technique that can underestimate its prevalence. For this reason, physicians aspire for an accurate, cost-effective, and noninvasive method to determine both the presence and the specific stage of the NAFLD. In this paper, we report an integrated approach for the quantitative estimation of the density of triglycerides in the liver based on the use of autofluorescence and reflectance signals generated by the abdomen of obese C57BL6/J mice. Singular value decomposition is applied to the generated spectra and its corresponding regression model provided a determination coefficient of 0.99 and a root mean square error of 240 mg/dl. This, in turn, enabled the quantitative imaging of triglycerides density in the livers of mice under in vivo conditions.

Multiparametric renal magnetic resonance imaging: A reproducibility study in renal allografts with stable function.

Monitoring renal allograft function after transplantation is key for the early detection of allograft impairment, which in turn can contribute to preventing the loss of the allograft. Multiparametric renal MRI (mpMRI) is a promising noninvasive technique to assess and characterize renal physiopathology; however, few studies have employed mpMRI in renal allografts with stable function (maintained function over a long time period). The purposes of the current study were to evaluate the reproducibility of mpMRI in transplant patients and to characterize normal values of the measured parameters, and to estimate the labeling efficiency of Pseudo-Continuous Arterial Spin Labeling (PCASL) in the infrarenal aorta using numerical simulations considering experimental measurements of aortic blood flow profiles. The subjects were 20 transplant patients with stable kidney function, maintained over 1 year. The MRI protocol consisted of PCASL, intravoxel incoherent motion, and T1 inversion recovery. Phase contrast was used to measure aortic blood flow. Renal blood flow (RBF), diffusion coefficient (D), pseudo-diffusion coefficient (D*), flowing fraction ( f ), and T1 maps were calculated and mean values were measured in the cortex and medulla. The labeling efficiency of PCASL was estimated from simulation of Bloch equations. Reproducibility was assessed with the within-subject coefficient of variation, intraclass correlation coefficient, and Bland-Altman analysis. Correlations were evaluated using the Pearson correlation coefficient. The significance level was p less than 0.05. Cortical reproducibility was very good for T1, D, and RBF, moderate for f , and low for D*, while medullary reproducibility was good for T1 and D. Significant correlations in the cortex between RBF and f (r = 0.66), RBF and eGFR (r = 0.64), and D* and eGFR (r = -0.57) were found. Normal values of the measured parameters employing the mpMRI protocol in kidney transplant patients with stable function were characterized and the results showed good reproducibility of the techniques.