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Short sub-100ms visual feedback latencies are common in many types of human-computer interactions yet are known to markedly reduce performance in a wide variety of motor tasks from simple pointing to operating surgical robotics. These latencies are also present in the computer-based experiments used to study the sensorimotor learning that underlies the acquisition of motor performance. Inspired by neurophysiological findings showing that cerebellar LTD and cortical LTP would both be disrupted by sub-100ms latencies, we hypothesized that implicit sensorimotor learning may be particularly sensitive to these short latencies. Remarkably, we find that improving latency by just 60ms, from 85 to 25ms in latency-optimized experiments, increases implicit learning by 50% and proportionally decreases explicit learning, resulting in a dramatic reorganization of sensorimotor memory. We go on to show that implicit sensorimotor learning is considerably more sensitive to latencies in the sub-100ms range than at higher latencies, in line with the latency-specific neural plasticity that has been observed. This suggests a clear benefit for latency reduction in computer-based training that involves implicit sensorimotor learning and that across-study differences in implicit motor learning might often be explained by disparities in feedback latency.
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Background: Primary type 2 hyperoxaluria is a very rare genetic disorder,1,2 where in the progression to renal failure was assumed to be insidious and not very common.3 PH2 is due to deficient glyoxylate reductase/hydroxypyruvate reductase (GRHPR),1,2 which was thought to have extra-hepatic production also.4 The progression to renal failure in these patient subgroups is well documented in the Literature and the role of SLK (simultaneous liver and kidney transplantation) has not been clearly established.8. Method: We present a case report of a young girl with PH2, who successfully underwent SLK, with evidence of reduction in the urine oxalate levels post SLK. Results: PH2, though a rare genetic disease, has a proven potential to progress to chronic renal failure requiring transplantation, renal transplantation alone has not shown any benefit, these patients can be offered SLK as a primary treatment option, to improve the outcomes, this needs further validation with consensus and studies.
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Purpose To perform a systematic review and meta-analysis to assess the prognostic value of stress perfusion cardiac MRI in predicting cardiovascular outcomes. Materials and Methods A systematic literature search from the inception of PubMed, Embase, Web of Science, and China National Knowledge Infrastructure until January 2023 was performed for articles that reported the prognosis of stress perfusion cardiac MRI in predicting cardiovascular outcomes. The quality of included studies was assessed using the Quality in Prognosis Studies tool. Reported hazard ratios (HRs) of univariable regression analyses with 95% CIs were pooled. Comparisons were performed across different analysis techniques (qualitative, semiquantitative, and fully quantitative), magnetic field strengths (1.5 T vs 3 T), and stress agents (dobutamine, adenosine, and dipyridamole). Results Thirty-eight studies with 58 774 patients with a mean follow-up time of 53 months were included. There were 1.9 all-cause deaths and 3.5 major adverse cardiovascular events (MACE) per 100 patient-years. Stress-inducible ischemia was associated with a higher risk of all-cause mortality (HR: 2.55 [95% CI: 1.89, 3.43]) and MACE (HR: 3.90 [95% CI: 2.69, 5.66]). For MACE, pooled HRs of qualitative, semiquantitative, and fully quantitative methods were 4.56 (95% CI: 2.88, 7.22), 3.22 (95% CI: 1.60, 6.48), and 1.78 (95% CI: 1.39, 2.28), respectively. For all-cause mortality, there was no evidence of a difference between qualitative and fully quantitative methods (P = .79). Abnormal stress perfusion cardiac MRI findings remained prognostic when subgrouped based on underlying disease, stress agent, and field strength, with HRs of 3.54, 2.20, and 3.38, respectively, for all-cause mortality and 3.98, 3.56, and 4.21, respectively, for MACE. There was no evidence of subgroup differences in prognosis between field strengths or stress agents. There was significant heterogeneity in effect size for MACE outcomes in the subgroups assessing qualitative versus quantitative stress perfusion analysis, underlying disease, and field strength. Conclusion Stress perfusion cardiac MRI is valuable for predicting cardiovascular outcomes, regardless of the analysis method, stress agent, or magnetic field strength used. Keywords: MR-Perfusion, MRI, Cardiac, Meta-Analysis, Stress Perfusion, Cardiac MR, Cardiovascular Disease, Prognosis, Quantitative © RSNA, 2024 Supplemental material is available for this article.
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Doenças Cardiovasculares , Humanos , Prognóstico , Doenças Cardiovasculares/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Imagem de Perfusão do Miocárdio/métodos , Teste de Esforço/métodosRESUMO
Endothelin (ET) receptor antagonists are being investigated in combination with sodium-glucose co-transporter-2 inhibitors (SGLT-2i). These drugs primarily inhibit the SGLT-2 transporter that, in humans, is thought to be mainly restricted to the renal proximal convoluted tubule, resulting in increased glucose excretion favouring improved glycaemic control and diuresis. This action reduces fluid retention with ET receptor antagonists. Studies have suggested SGLT-2 may also be expressed in cardiomyocytes of human heart. To understand the potential of combining the two classes of drugs, our aim was to compare the distribution of ET receptor sub-types in human kidney, with SGLT-2. Secondly, using the same experimental conditions, we determined if SGLT-2 expression could be detected in human heart and whether the transporter co-localised with ET receptors. METHODS: Immunocytochemistry localised SGLT-2, ETA and ETB receptors in sections of histologically normal kidney, left ventricle from patients undergoing heart transplantation or controls. Primary antisera were visualised using fluorescent microscopy. Image analysis was used to measure intensity compared with background in adjacent control sections. RESULTS: As expected, SGLT-2 localised to epithelial cells of the proximal convoluted tubules, and co-localised with both ET receptor sub-types. Similarly, ETA receptors predominated in cardiomyocytes; low (compared with kidney but above background) positive staining was also detected for SGLT-2. DISCUSSION: Whether low levels of SGLT-2 have a (patho)physiological role in cardiomyocytes is not known but results suggest the effect of direct blockade of sodium (and glucose) influx via SGLT-2 inhibition in cardiomyocytes should be explored, with potential for additive effects with ETA antagonists.
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Receptor de Endotelina A , Receptor de Endotelina B , Transportador 2 de Glucose-Sódio , Humanos , Rim/metabolismo , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/efeitos dos fármacos , Miocárdio/metabolismo , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/genética , Inibidores do Transportador 2 de Sódio-Glicose/farmacologiaRESUMO
Advancing imaging technologies are drastically increasing the rate of marine video and image data collection. Often these datasets are not analysed to their full potential as extracting information for multiple species is incredibly time-consuming. This study demonstrates the capability of the open-source interactive machine learning tool, RootPainter, to analyse large marine image datasets quickly and accurately. The ability of RootPainter to extract the presence and surface area of the cold-water coral reef associate sponge species, Mycale lingua, was tested in two datasets: 18 346 time-lapse images and 1420 remotely operated vehicle video frames. New corrective annotation metrics integrated with RootPainter allow objective assessment of when to stop model training and reduce the need for manual model validation. Three highly accurate M. lingua models were created using RootPainter, with an average dice score of 0.94 ± 0.06. Transfer learning aided the production of two of the models, increasing analysis efficiency from 6 to 16 times faster than manual annotation for time-lapse images. Surface area measurements were extracted from both datasets allowing future investigation of sponge behaviours and distributions. Moving forward, interactive machine learning tools and model sharing could dramatically increase image analysis speeds, collaborative research and our understanding of spatiotemporal patterns in biodiversity.
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Background: There is limited evidence of association of nirmatrelvir-ritonavir (NMV-r) and incidence of postacute sequelae of SARS-CoV-2 infection (PASC) in patients with pre-existing cardiovascular disease (CVD). Objectives: The objective of this study was to assess the association of NMV-r in nonhospitalized, vaccinated patients with pre-existing CVD and occurrence of PASC. Methods: We conducted a retrospective cohort study utilizing the TriNetX research network, including vaccinated patients with pre-existing CVD who developed COVID-19 between December 2021 and December 2022. Two cohorts were created based on NMV-r administration within 5 days of diagnosis: NMV-r and non-NMV-r cohort. The main outcome was presence of PASC, assessed between 30 to 90 days and 90 to 180 days after index COVID-19 infection. After propensity score matching, both cohorts were compared using t-test and chi-square test for continuous and categorical variables, respectively. Results: A total of 26,953 patients remained in each cohort after propensity score matching. Broadly defined PASC occurred in 6,925 patients (26%) in the NMV-r cohort vs 8,150 patients (30.6%) in the non-NMV-r cohort (OR: 0.80; 95% CI: 0.76-0.82; P < 0.001) from 30 to 90 days and in 6,692 patients (25.1%) as compared to 8,910 patients (33.5%) (OR: 0.25, 95% CI: 0.23-0.29; P < 0.001) from 90 to 180 days. Similarly, narrowly defined PASC occurred in 5,335 patients (20%) in the NMV-r cohort vs 6,271 patients (23.6%) in the non-NMV-r cohort between 30 and 90 days (OR: 0.81, 95% CI: 0.78-0.84, P < 0.001) and in 5,121 patients (19.2%) as compared to 6,964 patients (26.1%) (OR: 0.67, 95% CI: 0.64-0.70, P < 0.001) between 90 and 180 days. Conclusions: NMV-r in nonhospitalized vaccinated patients with pre-existing CVD with COVID-19 was associated with a reduction in PASC and health care utilization.
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Recent case reports and epidemiological data suggest that fungal infections represent an underappreciated complication among people with severe COVID-19. However, the frequency of fungal colonization in patients with COVID-19 and associations with specific immune responses in the airways remain incompletely defined. We previously generated a single-cell RNA-sequencing data set characterizing the upper respiratory microenvironment during COVID-19 and mapped the relationship between disease severity and the local behavior of nasal epithelial cells and infiltrating immune cells. Our previous study, in agreement with findings from related human cohorts, demonstrated that a profound deficiency in host immunity, particularly in type I and type III interferon signaling in the upper respiratory tract, is associated with rapid progression to severe disease and worse clinical outcomes. We have now performed further analysis of this cohort and identified a subset of participants with severe COVID-19 and concurrent detection of Candida species-derived transcripts within samples collected from the nasopharynx and trachea. Here, we present the clinical characteristics of these individuals. Using matched single-cell transcriptomic profiles of these individuals' respiratory mucosa, we identify epithelial immune signatures suggestive of IL17 stimulation and anti-fungal immunity. Further, we observe a significant expression of anti-fungal inflammatory cascades in the nasal and tracheal epithelium of all participants who went on to develop severe COVID-19, even among participants without detectable genetic material from fungal pathogens. Together, our data suggest that IL17 stimulation-in part driven by Candida colonization-and blunted interferon signaling represent a common feature of severe COVID-19 infection. IMPORTANCE: In this paper, we present an analysis suggesting that symptomatic and asymptomatic fungal coinfections can impact patient disease progression during COVID-19 hospitalization. By looking into the presence of other pathogens and their effect on the host immune response during COVID-19 hospitalizations, we aim to offer insight into an underestimated scenario, furthering our current knowledge of determinants of severity that could be considered for future diagnostic and intervention strategies.
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COVID-19 , Coinfecção , Células Epiteliais , Interferon Tipo I , Interleucina-17 , SARS-CoV-2 , Humanos , Interleucina-17/metabolismo , Interleucina-17/genética , Interleucina-17/imunologia , COVID-19/imunologia , Coinfecção/imunologia , Coinfecção/microbiologia , Coinfecção/virologia , Interferon Tipo I/metabolismo , Interferon Tipo I/imunologia , Masculino , SARS-CoV-2/imunologia , Pessoa de Meia-Idade , Feminino , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Adulto , Mucosa Nasal/imunologia , Mucosa Nasal/microbiologia , Idoso , Nasofaringe/microbiologia , Candidíase/imunologia , Candidíase/microbiologia , Micoses/imunologiaRESUMO
BACKGROUND: Neoadjuvant chemotherapy (NACT) with TPF (docetaxel, cisplatin, and 5FU) is one of the treatment options in very locally advanced oral cancer with a survival advantage over PF (cisplatin and 5FU). TP (docetaxel and cisplatin) has shown promising results with a lower rate of adverse events but has never been compared to TPF. METHODS: In this phase 3 randomized superiority study, adult patients with borderline resectable locally advanced oral cancers were randomized in a 1:1 fashion to either TP or TPF. After the administration of 2 cycles, patients were evaluated in a multidisciplinary clinic and further treatment was planned. The primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS) and adverse events. RESULTS: 495 patients were randomized in this study, 248 patients in TP arm and 247 in TPF arm. The 5-year OS was 18.5% (95% CI 13.8-23.7) and 23.9% (95% CI 18.1-30.1) in TP and TPF arms, respectively (Hazard ratio 0.778; 95% CI 0.637-0.952; P = 0.015). Following NACT, 43.8% were deemed resectable, but 34.5% underwent surgery. The 5-year OS was 50.7% (95% CI 41.5-59.1) and 5% (95%CI 2.9-8.1), respectively, in the surgically resected versus unresected cohort post NACT (P < 0.0001). Grade 3 or above adverse events were seen in 97 (39.1%) and 179 (72.5%) patients in the TP and TPF arms, respectively (P < 0.0001). CONCLUSION: NACT with TPF has a survival benefit over TP in borderline resectable oral cancers, with an increase in toxicity which is manageable. Patients who undergo surgery achieve a relatively good, sustained survival.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Adulto , Humanos , Docetaxel/uso terapêutico , Platina/uso terapêutico , Cisplatino , Terapia Neoadjuvante , Fluoruracila , Taxoides/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/cirurgia , Quimioterapia de Indução/métodos , Neoplasias de Cabeça e Pescoço/tratamento farmacológicoRESUMO
BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Studies have shown a strong association between non-alcoholic steatohepatitis (NASH) cirrhosis and portal vein thrombosis. Specifically, there is paucity of data on the association of NASH and venous thromboembolism (VTE), with one such study predicting a 2.5-fold increased risk for VTE compared to other liver diseases in hospitalized patients. The mechanism is believed to be a hepatocellular injury, which causes a chronic inflammatory state leading to the unregulated activation of procoagulant factors. There has been no prior analysis of the degree of steatosis and fibrosis (measured using transient elastography, commonly known as FibroScan) in NASH and its association with VTE. AIM: To examine the association between the degree of hepatic steatosis and fibrosis, quantified by transient elastography, and the incidence of VTE in patients with NASH. METHODS: In our case-control study, we included patients with a documented diagnosis of NASH. We excluded patients with inherited thrombophilia, hemoglobinopathy, malignancy, alcohol use disorder, autoimmune hepatitis, and primary biliary cirrhosis. The collected data included age, demographics, tobacco use, recreational drug use, medical history, and vibration controlled transient elastography scores. VTE-specific data included the location, type of anticoagulant, need for hospital stay, and history of VTE recurrence. Steatosis was categorized as S0-S1 (mild) and S2-S3 (moderate to severe) based on the controlled attenuation parameter score. Fibrosis was classified based on the kilopascal score and graded as F0-F1 (Metavir stage), F2, F3, and F4 (cirrhosis). χ2 and Mann-Whitney U tests were used for the qualitative and quantitative variable analyses, respectively. Furthermore, we performed a logistic regression using VTE as the dependent variable. RESULTS: A total of 415 patients were analyzed, and 386 met the inclusion criteria. 51 and 335 patients were included in the VTE and non-VTE groups, respectively. Patients with VTE had a mean age of 60.63 years compared to 55.22 years in the non-VTE group (P < 0.014). Patients with VTE had a higher body mass index (31.14 kg/m² vs 29.30 kg/m²) and a higher prevalence of diabetes mellitus (29.4% vs 13.1%). The history of NASH was significantly higher in the VTE group (45.1% vs 30.4%, P < 0.037). Furthermore, moderate-to-severe steatosis was significantly higher in the VTE group (66.7% vs 47.2%, P < 0.009). Similarly, the F2-F4 fibrosis grade had a prevalence of 58.8% in the VTE group compared to 38.5% in the non-VTE group (P < 0.006). On logistic regression, using VTE as a dependent variable, diabetes mellitus had an odds ratio (OR) =1.702 (P < 0.015), and F2-F4 fibrosis grade had an OR = 1.5 (P < 0.033). CONCLUSION: Our analysis shows that NASH is an independent risk factor for VTE, especially deep vein thrombosis. There was a statistically significant association between the incidence of VTE, moderate-to-severe steatosis, and fibrosis. All hospitalized patients should be considered for medical thromboprophylaxis, particularly those with NASH.
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BACKGROUND: Studies have shown elevated C-reactive protein (CRP) to predict mechanical ventilation (MV) in patients with coronavirus disease 2019 (COVID-19). Its utility is unknown in patients with chronic kidney disease (CKD), who have elevated baseline CRP levels due to chronic inflammation and reduced renal clearance. AIM: To assess whether an association exists between elevated inflammatory markers and MV rate in patients with stages IIIb-V CKD and COVID-19. METHODS: We conducted a retrospective cohort study on patients with COVID-19 and stages IIIb-V CKD. The primary outcome was the rate of invasive MV, the rate of noninvasive MV, and the rate of no MV. Statistical analyses used unpaired t-test for continuous variables and chi-square analysis for categorical variables. Cutoffs for variables were CRP: 100 mg/L, ferritin: 530 ng/mL, D-dimer: 0.5 mg/L, and lactate dehydrogenase (LDH): 590 U/L. RESULTS: 290 were screened, and 118 met the inclusion criteria. CRP, D-dimer, and ferritin were significantly different among the three groups. On univariate analysis for invasive MV (IMV), CRP had an odds ratio (OR)-5.44; ferritin, OR-2.8; LDH, OR-7.7; D-dimer, OR-3.9, (P < 0.05). The admission CRP level had an area under curve-receiver operator characteristic (AUROC): 0.747 for the IMV group (sensitivity-80.8%, specificity-50%) and 0.663 for the non-IMV (NIMV) group (area under the curve, sensitivity-69.2%, specificity-53%). CONCLUSION: Our results demonstrate a positive correlation between CRP, ferritin, and D-dimer levels and MV and NIMV rates in CKD patients. The AUROC demonstrates a good sensitivity for CRP levels in detecting the need for MV in patients with stages IIIb-V CKD. This may be because of the greater magnitude of increased inflammation due to COVID-19 itself compared with increased inflammation and reduced clearance due to CKD alone.
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The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.16177. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.