Host and fungal factors both contribute to cryptococcosis-associated hyperammonemia (cryptammonia).

Cryptococcus neoformans and Cryptococcus gattii are both known urease producers and have the potential to cause hyperammonemia. We hypothesized that the risk of hyperammonemia is increased by renal failure, burden of cryptococcal infection, and fungal strain characteristics. We performed a retrospective review of plasma ammonia levels in patients with cryptococcal infections. Risk factors for hyperammonemia were statistically compared between patients with and without hyperammonemia (>53 µmol/L). Cryptococcal cells from three patients included in the study were recovered from our biorepository. Strain characteristics including urease activity, ammonia production, growth curves, microscopy, melanin production, and M13 molecular typing were analyzed and compared with a wild-type (WT) C. neoformans strain. We included 29 patients, of whom 37.9% had hyperammonemia, 59% had disseminated cryptococcal infection (DCI), and 41% had isolated central nervous system infection. Thirty-eight percent of patients had renal failure and 28% had liver disease. Renal failure was associated with 4.4 times (95% confidence interval [CI] 1.5, 13.0) higher risk of hyperammonemia. This risk was higher in DCIs (RR 6.2, 95% CI 1.0, 40.2) versus isolated cryptococcal meningitis (RR 2.5, 95% CI, 0.40, 16.0). Liver disease and cryptococcal titers were not associated with hyperammonemia. C. neoformans from one patient with extreme hyperammonemia demonstrated a 4- to 5-fold increase in extracellular urease activity, slow growth, enlarged cell size phenotypes, and diminished virulence factors. Hyperammonemia was strongly associated with renal failure in individuals with DCI, surpassing associations with liver failure or cryptococcal titers. However, profound hyperammonemia in one patient was attributable to high levels of urease secretion unique to that cryptococcal strain. Prospective studies are crucial to exploring the significance of this association.IMPORTANCECryptococcus produces and secretes the urease enzyme to facilitate its colonization of the host. Urease breaks down urea into ammonia, overwhelming the liver's detoxification process and leading to hyperammonemia in some hosts. This underrecognized complication exacerbates organ dysfunction alongside the infection. Our study investigated this intricate relationship, uncovering a strong association between the development of hyperammonemia and renal failure in patients with cryptococcal infections, particularly those with disseminated infections. We also explore mechanisms underlying increased urease activity, specifically in strains associated with extreme hyperammonemia. Our discoveries provide a foundation for advancing research into cryptococcal metabolism and identifying therapeutic targets to enhance patient outcomes.

A category theory perspective on the Language of Thought: LoT is universal.

The Language of Thought (LoT) hypothesis proposes that some collections of mental states and processes are symbol systems to explain language-like systematic properties of thought. Recent proponents of this hypothesis point to additional LoT-like properties in non-linguistic domains to claim that LoT remains the "best game in town" in terms of explanatory coverage. Nonetheless, LoT assumes but does not explain why/how symbolic representations connect to other (non-symbolic) formats. The perspective presented here is supposed to bridge this gap as a duality in a category theoretical sense: (perceptual) data are projected onto a base (conceptual) space in one direction, and in the opposite direction, these data are referenced by that space. Accordingly, perception is dual to conception. These constructions follow from a universal mapping principle affording an explanation for why/how symbolic and non-symbolic formats are connected: as the "best" possible transformation between the two forms- so the slogan, LoT is universal. This view also sheds some light on the apparent pervasiveness of logic-like capacities across age-groups and species, and these constructions constitute special types of categories called toposes (topoi), and every topos has an interpretation in first-order logic.

Severe communication delays are independent of seizure burden and persist despite contemporary treatments in SCN1A+ Dravet syndrome: Insights from the ENVISION natural history study.

OBJECTIVE: Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by high seizure burden, treatment-resistant epilepsy, and developmental stagnation. Family members rate communication deficits among the most impactful disease manifestations. We evaluated seizure burden and language/communication development in children with DS. METHODS: ENVISION was a prospective, observational study evaluating children with DS associated with SCN1A pathogenic variants (SCN1A+ DS) enrolled at age ≤5 years. Seizure burden and antiseizure medications were assessed every 3 months and communication and language every 6 months with the Bayley Scales of Infant and Toddler Development 3rd edition and the parent-reported Vineland Adaptive Behavior Scales 3rd edition. We report data from the first year of observation, including analyses stratified by age at Baseline: 0:6-2:0 years:months (Y:M; youngest), 2:1-3:6 Y:M (middle), and 3:7-5:0 Y:M (oldest). RESULTS: Between December 2020 and March 2023, 58 children with DS enrolled at 16 sites internationally. Median follow-up was 17.5 months (range = .0-24.0), with 54 of 58 (93.1%) followed for at least 6 months and 51 of 58 (87.9%) for 12 months. Monthly countable seizure frequency (MCSF) increased with age (median [minimum-maximum] = 1.0 in the youngest [1.0-70.0] and middle [1.0-242.0] age groups and 4.5 [.0-2647.0] in the oldest age group), and remained high, despite use of currently approved antiseizure medications. Language/communication delays were observed early, and developmental stagnation occurred after age 2 years with both instruments. In predictive modeling, chronologic age was the only significant covariate of seizure frequency (effect size = .52, p = .024). MCSF, number of antiseizure medications, age at first seizure, and convulsive status epilepticus were not predictors of language/communication raw scores. SIGNIFICANCE: In infants and young children with SCN1A+ DS, language/communication delay and stagnation were independent of seizure burden. Our findings emphasize that the optimal therapeutic window to prevent language/communication delay is before 3 years of age.

Feasibility and Reliability of Transcranial POCUS Color-Coded Duplex Sonography Performed by Physicians of Varied Ultrasound Experience in Diagnosing Vasospasm in Aneurysmal Subarachnoid Hemorrhage.

PURPOSE: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high morbidity and mortality, which is largely attributable to secondary complications such as vasospasm and subsequent delayed cerebral ischemia. Transcranial Doppler (TCD) is recommended for the screening of vasospasm; however, technicians are not always available. We aimed to see how feasible and reliable bedside transcranial point-of-care ultrasound (POCUS) color-coded duplex sonography was compared with formal non-imaging TCD in measuring velocities and in diagnosing vasospasm. METHODS: This was a prospective observational study that took place in the neuroscience intensive care unit at a single academic medical center. Patients with aSAH who were undergoing formal TCDs were scanned on days 2-10 of their admission by physicians of ranging ultrasound experience. Absolute velocities were compared as well as the diagnosis of vasospasm via POCUS and formal TCDs. RESULTS: A total of 226 bedside ultrasound exams were performed and compared with 126 formal TCD studies. Sonographic windows were obtained in 89.4% of patients. Scans took 6.6 minutes to complete on average by the advanced group versus 14.5 minutes in the beginner. Correlation ranged from .52 in the beginner group to .65 in the advanced. When good quality of images obtained at a depth of 4-5 cm were reviewed, correlation of mean velocities increased to .96. Overall sensitivity for diagnosing vasospasm was 75%, with a specificity of 99% and negative predictive value of 99%. CONCLUSION: Overall, POCUS TCD cannot replace a formal study performed by expert sonographers. An abbreviated POCUS scan can be performed quickly, however, particularly with more experienced operators. POCUS TCD can also feasibly detect vasospasm, and accurate velocities can be obtained by those with all levels of ultrasound experience. Care must be taken on image interpretation that velocities are obtained at an appropriate depth to ensure appropriate insonation of the MCA as well as in optimal alignment with the vessel to obtain the most accurate velocities.

Complete Heart Block After Low Dose Octreotide Infusion for Esophageal Variceal Bleeding.

Cirrhosis and chronic liver disease cause a myriad of systemic health problems mostly caused by the presence of portal hypertension. Esophageal varices are one result of portal hypertension. They can rupture and bleed, which can be catastrophic in already coagulopathic liver failure patients. We present a patient who presented with decompensated liver failure for transplant. He developed a severe and refractory gastrointestinal bleed and was put on an octreotide infusion to increase splanchnic flow and decrease portal pressures. He subsequently developed complete heart block. Understanding the mechanisms of octreotide is imperative due to its frequent use in medically complex patients.

Evaluating the Distinction between Cool and Hot Executive Function during Childhood.

This article assesses the cool-hot executive function (EF) framework during childhood. First, conceptual analyses suggest that cool EF (cEF) is generally distinguished from hot EF (hEF). Second, both EFs can be loaded into different factors using confirmatory factor analyses. Third, the cognitive complexity of EF is similar across cEF tasks, and the cognitive complexity of cEF is similar to hEF tasks. Finally, neuroimaging analysis suggests that children activate the lateral prefrontal regions during all EF tasks. Taken together, we propose that the cool-hot framework is a useful, though not definitive way of characterizing differences in EF.

What is category theory to cognitive science? Compositional representation and comparison.

Category theorists and cognitive scientists study the structural (analogical) relations between domains of interest albeit in different contexts, that is, formal and psychological systems, respectively. Despite this basic commonality, very few cognitive scientists take a category theory approach toward understanding the structure of cognition which raises the question, What is category theory to cognitive science? An answer is given as the slogan "Category theory is to cognitive science as functor is to representation; as natural transformation is to comparison" to make category theory more accessible and informative for cognitive scientists.

A Case of "Cryptammonia": Disseminated Cryptococcal Infection Generating Profound Hyperammonemia in a Liver Transplant Recipient.

Mycoplasma and Ureaplasma infections have been described as a cause of hyperammonemia syndrome leading to devastating neurological injury in the post-transplant period, most commonly in lung transplant recipients. The occurrence of significant hyperammonemia caused by other urease-producing organisms remains unclear. We describe a case of disseminated cryptococcosis presenting with profound hyperammonemia in a 55-year-old orthotopic liver transplant recipient. Through a process of elimination, other potential causes for hyperammonemia were excluded revealing a probable association between hyperammonemia and disseminated cryptococcosis.

Enriched category as a model of qualia structure based on similarity judgements.

Qualitative relationships between two instances of conscious experiences can be quantified through the perceived similarity. Previously, we proposed that by defining similarity relationships as arrows and conscious experiences as objects, we can define a category of qualia in the context of category theory. However, the example qualia categories we proposed were highly idealized and limited to cases where perceived similarity is binary: either present or absent without any gradation. Here, we introduce enriched category theory to address the graded levels of similarity that arises in many instances of qualia. Enriched categories generalize the concept of a relation between objects as a directed arrow (or morphism) in ordinary category theory to a more flexible notion, such as a measure of distance. As an alternative relation, here we propose a graded measure of perceived dissimilarity between the two objects. We claim that enriched categories accommodate various types of conscious experiences. An important consequence of this claim is the application of the Yoneda lemma in enriched category; we can characterize a quale through a collection of relationships between the quale and the other qualia up to an (enriched) isomorphism.

An adjunction hypothesis between qualia and reports.

What are the nature of the relationship among qualia, contents of consciousness, and behavioral reports? Traditionally, this type of question has been only addressed via a qualitative and philosophical approach. Some theorists emphasize an incomplete and inaccurate nature of reports of one's own qualia to discourage formal research programs on qualia. Other empirical researchers, however, have made substantial progress in understanding the structure of qualia from such limited reports. What is the precise relationship between the two? To answer this question, we introduce the concept of "adjoint" or "adjunction" from the category theory in mathematics. We claim that the adjunction captures some aspects of the nuanced relationships between qualia and reports. The concept of adjunction allows us to clarify the conceptual issues with a precise mathematical formulation. In particular, adjunction establishes coherence between two categories that cannot be considered equivalent, yet has an important relationship. This rises in empirical experimental situations between qualia and reports. More importantly, an idea of adjunction naturally leads to various proposals of new empirical experiments to test the predictions about the nature of their relationship as well as other issues in consciousness research.

Growth factors for treating chronic venous leg ulcers: A systematic review and meta-analysis.

Chronic venous leg ulcers (VLU) are wounds that commonly occur due to venous insufficiency. Many growth factors have been introduced over the past two decades to treat VLU. This systematic review and meta-analysis evaluates the impact of growth factor treatments of VLU in comparison to control for complete wound healing, percent reduction in wound area, time to wound healing, and adverse events. A systematic review and meta-analysis of randomised trials was conducted. MEDLINE and EMBASE were searched up to December 2020. Studies were included if they compared a growth factor versus placebo or standard care in patients with VLU. From 1645 articles, 13 trials were included (n = 991). There was a significant difference between any growth factor and placebo in complete wound healing (P = 0.04). Any growth factor compared to placebo significantly increased the likelihood of percent wound reduction by 48.80% (P = <0.00001). There was no difference in overall adverse event rate. Most comparisons have low certainty of evidence according to Grading of Recommendations, Assessment, Development, and Evaluation. This meta-analysis suggests that growth factors have a beneficial effect in complete wound healing of VLU. Growth factors may also increase percent reduction in wound area. The suggestion of benefit for growth factors identified in this review is not a strong one based on the low quality of evidence.

Public Perspectives on COVID-19 Vaccine Prioritization.

Importance: As COVID-19 vaccine distribution continues, policy makers are struggling to decide which groups should be prioritized for vaccination. Objective: To assess US adults' preferences regarding COVID-19 vaccine prioritization. Design, Setting, and Participants: This survey study involved 2 independent, online surveys of US adults aged 18 years and older, 1 conducted by Gallup from September 14 to 27, 2020, and the other conducted by the COVID Collaborative from September 19 to 25, 2020. Samples were weighted to reflect sociodemographic characteristics of the US population. Exposures: Respondents were asked to prioritize groups for COVID-19 vaccine and to rank their prioritization considerations. Main Outcomes and Measures: The study assessed prioritization preferences and agreement with the National Academies of Science, Engineering, and Medicine's Preliminary Framework for Equitable Allocation of COVID-19 Vaccine. Results: A total of 4735 individuals participated, 2730 (1474 men [54.1%]; mean [SD] age, 59.2 [14.5] years) in the Gallup survey and 2005 (944 men [47.1%]; 203 participants [21.5%] aged 55-59 years) in the COVID Collaborative survey. In both the Gallup COVID-19 Panel and COVID Collaborative surveys, respondents listed health care workers (Gallup, 93.6% [95% CI, 91.2%-95.3%]; COVID Collaborative, 80.0% [95% CI, 78.0%-81.9%]) and adults of any age with serious comorbid conditions (Gallup, 78.6% [95% CI, 75.2%-81.7%]; COVID Collaborative, 72.9% [95% CI, 70.7%-74.9%]) among their 4 highest priority groups. Respondents of all political affiliations agreed with prioritizing Black, Hispanic, Native American, and other communities that have been disproportionately affected by COVID-19 (Gallup, 74.2% [95% CI, 70.6%-77.5%]; COVID Collaborative, 84.9% [95% CI, 83.1%-86.5%]), and COVID Collaborative respondents were willing to be preceded in line by teachers and childcare workers (92.5%; 95% CI, 91.2%-93.7%) and grocery workers (85.9%; 95% CI, 84.2%-87.5%). Older respondents in both surveys were significantly less likely than younger respondents to prioritize healthy adults aged 65 years and older among their 4 highest priority groups (Gallup, 23.7% vs 39.1% [χ2 = 2160.8; P < .001]; COVID Collaborative, 23.3% vs 28.8% [χ2 = 5.0198; P = .03]). COVID Collaborative respondents believed the 4 most important considerations for prioritization were preventing COVID-19 spread (78.4% [95% CI, 76.3%-80.3%]), preventing the most deaths (72.1% [95% CI, 69.9%-74.2%]), preventing long-term complications (68.9% [66.6%-71.9%]), and protecting frontline workers (63.8% [95% CI, 61.5%-66.1%]). Conclusions and Relevance: US adults broadly agreed with the National Academies of Science, Engineering, and Medicine's prioritization framework. Respondents endorsed prioritizing racial/ethnic communities that are disproportionately affected by COVID-19, and older respondents were significantly less likely than younger respondents to endorse prioritizing healthy people older than 65 years. This provides reason for caution about COVID-19 vaccine distribution plans that prioritize healthy adults older than a cutoff age without including those younger than that age with preexisting conditions, that aim solely to prevent the most deaths, or that give no priority to frontline workers or disproportionately affected communities.

A reconstruction theory of relational schema induction.

Learning transfer (i.e. accelerated learning over a series of structurally related learning tasks) differentiates species and age-groups, but the evolutionary and developmental implications of such differences are unclear. To this end, the relational schema induction paradigm employing tasks that share algebraic (group-like) structures was introduced to contrast stimulus-independent (relational) versus stimulus-dependent (associative) learning processes. However, a theory explaining this kind of relational learning transfer has not been forthcoming beyond a general appeal to some form of structure-mapping, as typically assumed in models of analogy. In this paper, we provide a theory of relational schema induction as a "reconstruction" process: the algebraic structure underlying transfer is reconstructed by comparing stimulus relations, learned within each task, for structural consistency across tasks-formally, the theory derives from a category theory version of Tannakian reconstruction. The theory also applies to non-human studies of relational concepts, thereby placing human and non-human transfer on common ground for sharper comparison and contrast. As the theory and paradigm do not depend on linguistic ability, we also have a way for pinpointing where aspects of human learning diverge from other species without begging the question of language.

Modification of a domiciliary ventilator to increase FiO2: an off-label modification which may be of value in COVID-19.

Although nasal continuous positive airway pressure or non-invasive ventilation is used to manage some patients with acute lung injury due to COVID-19, such patients also demonstrate increased minute ventilation which makes it hard, if the device is used in line with the manufacturer's instructions, to achieve adequate oxygen delivery. In addition, if a hospital contains many such patients, then it is possible that the oxygen requirements will exceed infrastructure capacity. Here we describe a simple modification of two exemplar ventilators normally used for domiciliary ventilation, which substantially increased the fraction of inspired oxygen (FiO2) delivered.