Rapid Whole-Genome Sequencing and Clinical Management in the PICU: A Multicenter Cohort, 2016-2023.

OBJECTIVES: Analysis of the clinical utility of rapid whole-genome sequencing (rWGS) outside of the neonatal period is lacking. We describe the use of rWGS in PICU and cardiovascular ICU (CICU) patients across four institutions. DESIGN: Ambidirectional multisite cohort study. SETTING: Four tertiary children's hospitals. PATIENTS: Children 0-18 years old in the PICU or CICU who underwent rWGS analysis, from May 2016 to June 2023. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 133 patients underwent clinical, phenotype-driven rWGS analysis, 36 prospectively. A molecular diagnosis was identified in 79 patients (59%). Median (interquartile range [IQR]) age was 6 months (IQR 1.2 mo-4.6 yr). Median time for return of preliminary results was 3 days (IQR 2-4). In 79 patients with a molecular diagnosis, there was a change in ICU management in 19 patients (24%); and some change in clinical management in 63 patients (80%). Nondiagnosis changed management in 5 of 54 patients (9%). The clinical specialty ordering rWGS did not affect diagnostic rate. Factors associated with greater odds ratio (OR [95% CI]; OR [95% CI]) of diagnosis included dysmorphic features (OR 10.9 [95% CI, 1.8-105]) and congenital heart disease (OR 4.2 [95% CI, 1.3-16.8]). Variables associated with greater odds of changes in management included obtaining a genetic diagnosis (OR 16.6 [95% CI, 5.5-62]) and a shorter time to genetic result (OR 0.8 [95% CI, 0.76-0.9]). Surveys of pediatric intensivists indicated that rWGS-enhanced clinical prognostication (p < 0.0001) and contributed to a decision to consult palliative care (p < 0.02). CONCLUSIONS: In this 2016-2023 multiple-PICU/CICU cohort, we have shown that timely genetic diagnosis is feasible across institutions. Application of rWGS had a 59% (95% CI, 51-67%) rate of diagnostic yield and was associated with changes in critical care management and long-term patient management.

Neuropsychological correlates of visual hallucinatory phenomena in Lewy body disease.

OBJECTIVES: Visual hallucinations (VH) ranging from minor to complex, are the most common psychiatric feature of Lewy Body Disease (LBD). Despite their high prevalence and poor prognostic implications instigating extensive research, the precise mechanisms underlying VH remain unclear. Cognitive impairment (CI) is a risk factor and a consistent correlate of VH in LBD. To help shed light on their underlying mechanisms, this study investigates the pattern of CI across the spectrum of VH in LBD. METHODS: 30 LBD patients with minor VH (MVH), 13 with complex VH (CVH) and 32 without VH were retrospectively compared on the domains of higher-order visual processing, memory, language and executive functioning. The VH groups were further stratified to investigate whether phenomenological subtypes have distinct cognitive correlates. RESULTS: LBD patients with CVH were impaired on the visuo-spatial and executive functioning domains relative to controls. LBD patients with MVH were also impaired on the visuo-spatial domain. No differences emerged in cognitive domains affected between patient groups endorsing specific hallucinatory phenomena. CONCLUSION: A pattern of CI indicating fronto-subcortical dysfunction in combination with posterior cortical involvement is implicated in the genesis of CVH. Moreover, this posterior cortical dysfunction may precede the occurrence of CVH as indicated by selective visuo-spatial deficits in LBD patients with MVH.

A Bayesian predictive processing account of Othello syndrome in Parkinson's disease.

Introduction: Although delusions in Parkinson's disease (PD) are rare, when they occur they frequently take the form of "Othello syndrome": the irrational belief that a spouse or partner is being unfaithful. Hitherto dismissed as either a by-product of dopamine therapy or cognitive impairment, there are still no convincing theoretical accounts to explain why only some patients fall prey to this delusion, or why it persists despite clear disconfirmatory evidence.Methods: We discuss the limitations of existing explanations of this delusion, namely hyperdopaminergia-induced anomalous perceptual experiences and cognitive impairment, before describing how Bayesian predictive processing accounts can provide a more comprehensive explanation by foregrounding the importance of prior experience and its impact upon computation of probability. We illustrate this new conceptualisation with three case vignettes.Results: We suggest that in those with prior experience of romantic betrayal, hyperdominergic-induced aberrant prediction errors enable anomalous perceptual experiences to accrue greater prominence, which is then maintained through Bayes-optimal inferencing to confirm cognitive distortions, eliciting and shaping this dangerous delusion.Conclusions: We propose the first comprehensive mechanistic account of Othello syndrome in PD and discuss implications for clinical interventions.

Peripheral IV Administration of Hypertonic Saline: Single-Center Retrospective PICU Study.

OBJECTIVES: To determine the frequency and characteristics of complications of peripherally administered hypertonic saline (HTS) through assessment of infiltration and extravasation. DESIGN: Retrospective cross-sectional study. SETTING: Freestanding tertiary care pediatric hospital. PATIENTS: Children who received HTS through a peripheral IV catheter (PIVC). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We conducted a single-center retrospective review from January 2012 to 2019. A total of 526 patients with 1,020 unique administrations of HTS through a PIVC met inclusion criteria. The primary endpoint was PIVC failure due to infiltration or extravasation. The indication for the administration of HTS infusion was collected. Catheter data was captured, including the setting of catheter placement, anatomical location on the patient, gauge size, length of time from catheter insertion to HTS infusion, in situ duration of catheter lifespan, and removal rationale. The administration data for HTS was reviewed and included volume of administration, bolus versus continuous infusion, infusion rate, infusion duration, and vesicant medications administered through the PIVC. There were 843 bolus infusions of HTS and 172 continuous infusions. Of the bolus administrations, there were eight infiltrations (0.9%). The continuous infusion group had 13 infiltrations (7.6%). There were no extravasations in either group, and no patients required medical therapy or intervention by the wound care or plastic surgery teams. There was no significant morbidity attributed to HTS administration in either group. CONCLUSIONS: HTS administered through a PIVC infrequently infiltrates in critically ill pediatric patients. The infiltration rate was low when HTS is administered as a bolus but higher when given as a continuous infusion. However, no patient suffered an extravasation injury or long-term morbidity from any infiltration.

Long-term cognitive and psychosocial outcomes in adults with phenylketonuria.

Previous studies have suggested that cognitive and psychosocial underfunctioning in early-treated adults with phenylketonuria (PKU) may be explained by suboptimal adherence to dietary treatments, however, these studies often employ small samples, with different outcome measures, definitions and cut-offs. Samples have also tended to comprise participants with a limited range of blood phenylalanine concentrations, and often individuals who may not have been treated early enough to avoid neurological damage. In this study, we explore the impact of lifetime dietary control, as indicated by blood phenylalanine concentrations in childhood, adolescence and adulthood, on long-term cognitive and psychosocial outcomes in a large sample of adults with PKU who were diagnosed by neonatal screening and commenced on dietary treatment within the first month of life. One hundred and fifty-four participants underwent cognitive testing, assessing attention, learning, working memory, language, executive functioning and processing speed. One hundred and forty-nine completed measures of psychosocial functioning, documenting educational, occupational, quality of life, emotional and social outcomes which were compared with a group of healthy controls. Many adults with PKU demonstrated cognitive impairments, most frequently affecting processing speed (23%), executive function (20%) and learning (12%). Cognitive outcomes were related to measures of historic metabolic control, but only processing speed was significantly related to phenylalanine concentration at the time of testing after controlling for historic levels. Adults with PKU did not, however, differ from controls in educational, occupational, quality of life or emotional outcomes, or on a measure of family functioning, and showed only minor differences in relationship style. These findings have implications for patient counselling and decisions regarding the management of PKU in adulthood.

Clinical application of cell-free next-generation sequencing for infectious diseases at a tertiary children's hospital.

BACKGROUND: Children affected by infectious diseases may not always have a detectable infectious etiology. Diagnostic uncertainty can lead to prolonged hospitalizations, inappropriately broad or extended courses of antibiotics, invasive diagnostic procedures, and difficulty predicting the clinical course and outcome. Cell-free plasma next-generation sequencing (cfNGS) can identify viral, bacterial, and fungal infections by detecting pathogen DNA in peripheral blood. This testing modality offers the ability to test for many organisms at once in a shotgun metagenomic approach with a rapid turnaround time. We sought to compare the results of cfNGS to conventional diagnostic test results and describe the impact of cfNGS on clinical care in a diverse pediatric population at a large academic children's hospital. METHODS: We performed a retrospective chart review of hospitalized subjects at a tertiary pediatric hospital to determine the diagnostic yield of cfNGS and its impact on clinical care. RESULTS: We describe the clinical application of results from 142 cfNGS tests in the management of 110 subjects over an 8-month study period. In comparison to conventional testing as a reference standard, cfNGS was found to have a positive percent agreement of 89.6% and negative percent agreement of 52.3%. Furthermore, 32.4% of cfNGS results were directly applied to make a clinical change in management. CONCLUSIONS: We demonstrate the clinically utility of cfNGS in the management of acutely ill children. Future studies, both retrospective and prospective, are needed to clarify the optimal indications for testing.

Anaphylaxis-a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis.

Anaphylaxis is an acute, potential life-threatening systemic allergic reaction that may have a wide range of clinical manifestations. Severe anaphylaxis and/or the need for repeated doses of epinephrine to treat anaphylaxis are risk factors for biphasic anaphylaxis. Antihistamines and/or glucocorticoids are not reliable interventions to prevent biphasic anaphylaxis, although evidence supports a role for antihistamine and/or glucocorticoid premedication in specific chemotherapy protocols and rush aeroallergen immunotherapy. Evidence is lacking to support the role of antihistamines and/or glucocorticoid routine premedication in patients receiving low- or iso-osmolar contrast material to prevent recurrent radiocontrast media anaphylaxis. Epinephrine is the first-line pharmacotherapy for uniphasic and/or biphasic anaphylaxis. After diagnosis and treatment of anaphylaxis, all patients should be kept under observation until symptoms have fully resolved. All patients with anaphylaxis should receive education on anaphylaxis and risk of recurrence, trigger avoidance, self-injectable epinephrine education, referral to an allergist, and be educated about thresholds for further care.

Presence phenomena in parkinsonian disorders: Phenomenology and neuropsychological correlates.

INTRODUCTION: The feeling of a presence that occurs in the absence of objectively identifiable stimuli is common in parkinsonian disorders. Although previously considered benign and insignificant, recent evidence suggests that presence phenomena may act as the gateway to more severe hallucinations and dementia. Despite this, we still know relatively little about these phenomena. OBJECTIVE: To examine parkinsonian disorder patients' subjective experience of presence phenomena, and retrospectively analyse their cognitive correlates, in order to elucidate the emergence of information processing deficits in parkinsonian disorders. METHODS/DESIGN: 25 patients who endorsed presence phenomena were asked to complete a semi-structured interview about their experiences. The cognitive profiles of these patients were then compared to those of age- and education-matched patients who denied presence phenomena. RESULTS: Patients described the presence as mostly that of an unknown human with neutral valence. Patients who described it as unpleasant were noted to also demonstrate elevated anxiety. Patients who identified the presence as a known person, described it as touching them, or interacted with the presence emotionally or physically demonstrated reduced insight. Patients with presence phenomena demonstrated more frequent impairments in visual processing, executive function and speed of processing. CONCLUSIONS: Presence phenomena occur in the company of advancing cognitive impairment and involvement of the posterior cortical functions. Initially encountered as a neutral spatial skeleton, the experience is then shaped by the patient's affective state and level of insight.

Identification of a new-to-science cyanobacterium, Toxifilum mysidocida gen. nov. & sp. nov. (Cyanobacteria, Cyanophyceae).

Cyanobacteria occupy many niches within terrestrial, planktonic, and benthic habitats. The diversity of habitats colonized, similarity of morphology, and phenotypic plasticity all contribute to the difficulty of cyanobacterial identification. An unknown marine filamentous cyanobacterium was isolated from an aquatic animal rearing facility having mysid mortality events. The cyanobacterium originated from Corpus Christi Bay, TX. Filaments are rarely solitary, benthic mat forming, unbranched, and narrowing at the ends. Cells are 2.1 × 3.1 µm (width × length). Thylakoids are peripherally arranged on the outer third of the cell; cyanophycin granules and polyphosphate bodies are present. Molecular phylogenetic analysis in addition to morphology (transmission electron microscopy and scanning electron microscopy) and chemical composition all confirm it as a new genus and species we name Toxifilum mysidocida. At least one identified Leptolyngbya appears (based on genetic evidence and TEM) to belong to this new genus.

Relationship of Cognitive Function to Motor Symptoms and Mood Disorders in Patients With Isolated Dystonia.

OBJECTIVE: To investigate the relationship of dystonia symptoms to cognitive function by comparing cognitive performance in patients with focal (cervical) and generalized dystonia subtypes and examining the differential contributions of severity of symptoms and mood disorders to cognition. BACKGROUND: Studies of the nonmotor syndrome in isolated dystonia have reported evidence of cognitive dysfunction, but the cause of this impairment remains unclear. Several studies have suggested that poor cognitive performance reflects the distracting effects of the motor symptoms and/or a mood disorder. METHODS: In this retrospective study, we used an extensive battery of cognitive and mood assessments to compare 25 patients with cervical dystonia, 13 patients with generalized dystonia, and 50 healthy controls. RESULTS: We found cognitive performance to be independent of all clinical and mood variables. We found no significant differences in cognition between the two dystonia groups. The combined dystonia groups had significant impairment on only one measure of cognitive function, the Trail Making Test. Two patients were also impaired on the Stroop test, and six on the Hayling Sentence Completion Test. CONCLUSIONS: The nonmotor features of dystonia include subtle cognitive symptoms and high rates of mood disorders, both of which occur independent of motor symptom severity and level of disability. Thus, we would argue that isolated dystonia is a tripartite disorder, with motor, affective, and subtle cognitive features.

No dual-task practice effect in Alzheimer's disease.

Diagnosis of Alzheimer's disease (AD) requires evidence of progressive decline in cognitive function. However, many tests used to assess cognitive function suffer from considerable practice effects, reducing their reliability. Several studies have reported that the ability to do two things at once, or dual tasking, is impaired in AD, but unaffected by healthy ageing. The apparent specificity of this impairment suggests that this assessment may be particularly useful in the early diagnosis of AD, but the reliability of this assessment remains unknown. Therefore, this study investigated simultaneous performance of digit recall and tracking tasks across six testing sessions in eight people with AD, eight healthy older adults and eight healthy younger adults. The results found that dual-task performance was unaffected by healthy ageing, but significantly impaired in AD, with no effect of repeated exposure. The absence of any improvements in performance despite increased familiarity with the task's demands suggests that not only is the dual-task assessment well suited for monitoring progression over time, but also that dual tasking involves a specific cognitive function which is impaired in the AD brain.

The influence of working memory and processing speed on other aspects of cognitive functioning in de novo Parkinson's disease: Initial findings from network modelling and graph theory.

Deficits in working memory (WM) and processing speed (PS) are thought to undermine other cognitive functions in de novo Parkinson's disease (dnPD). However, these interrelationships are only partially understood. This study investigated whether there are stronger relationships between verbal WM and verbal episodic memory encoding and retrieval, whether verbal WM and PS have a greater influence on other aspects of cognitive functioning, and whether the overall strength of interrelationships among several cognitive functions differs in dnPD compared to health. Data for 198 healthy controls (HCs) and 293 dnPD patients were analysed. Participants completed a neuropsychological battery probing verbal WM, PS, verbal episodic memory, semantic memory, language and visuospatial functioning. Deficit analysis, network modelling and graph theory were combined to compare the groups. Results suggested that verbal WM performance, while slightly impaired, was more strongly associated with measures of verbal episodic memory encoding and retrieval, as well as other measured cognitive functions in the dnPD network model compared to the HC network model. PS task performance was impaired and more strongly associated with other neuropsychological task scores in the dnPD model. Associations among task scores were stronger overall in the dnPD model. Together, these results provide further evidence that WM and PS are important influences on the other aspects of cognitive functioning measured in this study in dnPD. Moreover, they provide novel evidence that verbal WM and PS might bear greater influence on the other measured cognitive functions and that these functions are more strongly intertwined in dnPD compared to health.

Application of cell-free plasma next-generation sequencing technology in the diagnosis and management of pediatric meningitis.

This retrospective study evaluates the clinical utility of CFPNGS in the diagnosis and management of pediatric meningitis. CFPNGS identified a causative pathogen in 36% of 28 subjects, compared to 50% for diverse conventional testing (57% combined). CFPNGS may be considered as an adjunct to standard testing.

Preventing and Controlling Zinc Deficiency Across the Life Course: A Call to Action.

Through diverse roles, zinc determines a greater number of critical life functions than any other single micronutrient. Beyond the well-recognized importance of zinc for child growth and resistance to infections, zinc has numerous specific roles covering the regulation of glucose metabolism, and growing evidence links zinc deficiency with increased risk of diabetes and cardiometabolic disorders. Zinc nutriture is, thus, vitally important to health across the life course. Zinc deficiency is also one of the most common forms of micronutrient malnutrition globally. A clearer estimate of the burden of health disparity attributable to zinc deficiency in adulthood and later life emerges when accounting for its contribution to global elevated fasting blood glucose and related noncommunicable diseases (NCDs). Yet progress attenuating its prevalence has been limited due, in part, to the lack of sensitive and specific methods to assess human zinc status. This narrative review covers recent developments in our understanding of zinc's role in health, the impact of the changing climate and global context on zinc intake, novel functional biomarkers showing promise for monitoring population-level interventions, and solutions for improving population zinc intake. It aims to spur on implementation of evidence-based interventions for preventing and controlling zinc deficiency across the life course. Increasing zinc intake and combating global zinc deficiency requires context-specific strategies and a combination of complementary, evidence-based interventions, including supplementation, food fortification, and food and agricultural solutions such as biofortification, alongside efforts to improve zinc bioavailability. Enhancing dietary zinc content and bioavailability through zinc biofortification is an inclusive nutrition solution that can benefit the most vulnerable individuals and populations affected by inadequate diets to the greatest extent.

Improving Conversations about Parkinson's Dementia.

BACKGROUND: People with Parkinson's disease (PD) have an increased risk of dementia, yet patients and clinicians frequently avoid talking about it due to associated stigma, and the perception that "nothing can be done about it". However, open conversations about PD dementia may allow people with the condition to access treatment and support, and may increase participation in research aimed at understanding PD dementia. OBJECTIVES: To co-produce information resources for patients and healthcare professionals to improve conversations about PD dementia. METHODS: We worked with people with PD, engagement experts, artists, and a PD charity to open up these conversations. 34 participants (16 PD; 6 PD dementia; 1 Parkinsonism, 11 caregivers) attended creative workshops to examine fears about PD dementia and develop information resources. 25 PD experts contributed to the resources. RESULTS: While most people with PD (70%) and caregivers (81%) shared worries about cognitive changes prior to the workshops, only 38% and 30%, respectively, had raised these concerns with a healthcare professional. 91% of people with PD and 73% of caregivers agreed that PD clinicians should ask about cognitive changes routinely through direct questions and perform cognitive tests at clinic appointments. We used insights from the creative workshops, and input from a network of PD experts to co-develop two open-access resources: one for people with PD and their families, and one for healthcare professionals. CONCLUSION: Using artistic and creative workshops, co-learning and striving for diverse voices, we co-produced relevant resources for a wider audience to improve conversations about PD dementia.

Genotype and phenotype in Parkinson's disease: lessons in heterogeneity from deep brain stimulation.

Variation in the genetic risk(s) of developing Parkinson's disease (PD) undoubtedly contributes to the subsequent phenotypic heterogeneity. Although patients with PD who undergo deep brain stimulation (DBS) are a skewed population, they represent a valuable resource for exploring the relationships between heterogeneous phenotypes and PD genetics. In this series, 94 patients who underwent DBS were screened for mutations in the most common genes associated with PD. The consequent genetic subgroups of patients were compared with respect to phenotype, levodopa (l-dopa), and DBS responsiveness. An unprecedented number (29%) of patients tested positive for at least 1 of the currently known PD genes. Patients with Parkin mutations presented at the youngest age but had many years of disease before needing DBS, whereas glucocerebrosidase (GBA) mutation carriers reached the threshold of needing DBS earlier, and developed earlier cognitive impairment after DBS. DBS cohorts include large numbers of gene positive PD patients and can be clinically instructive in the exploration of genotype-phenotype relationships.

Lifespan normative data (18-89 years) for Raven's Advanced Progressive Matrices Set I.

Raven's Advanced Progressive Matrices (APM) Set I is a validated and brief test of fluid intelligence, ideal for use in busy clinical settings. However, there is a dearth of normative data allowing an accurate interpretation of APM scores. To address this, we present normative data from across the adult lifespan (18-89 years) for the APM Set I. Data are presented in five age cohorts (total N = 352), including two older adult cohorts (65-79 years and 80-89 years), which allows age-standardized assessment. We also present data from a validated measure of premorbid intellectual ability, which was absent from previous standardizations of longer forms of the APM. In line with previous findings, a striking age-related decline was noted, beginning relatively early in adulthood and most marked amongst lower-scoring individuals. Older adults did not demonstrate difficulty with specific test items or make an increased proportion of specific errors. Sex was not a significant predictor of performance. The data set is of particular use in the neuropsychological assessment of older adults, given the known susceptibility of fluid intelligence to both the effects of normal ageing and acquired brain injury in older age. The results are discussed in light of theories of neurological ageing.

Transforming Nigerian Food Systems Through Their Backbones: Lessons From a Decade of Staple Crop Biofortification Programing.

This article presents the evolution of the biofortification program in Nigeria over the last decade and the role of interdisciplinary research in informing cost-effective, efficient, and inclusive development; implementation; and scaling of this program. Launched in 2011 to improve Nigeria's food systems to deliver accessible and affordable nutrients through commonly consumed staples, the Nigeria biofortification program was implemented through an effective partnership between the CGIAR and public, private, and civil society sectors at federal, state, and local levels. By the end of 2021, several biofortified varieties of Nigeria's 2 main staples, namely cassava and maize, were officially released for production by smallholders, with several biofortified varieties of other key staples (including pearl millet, rice, and sorghum) either under testing or in the release pipeline. In 2021, the program was estimated to benefit 13 million Nigerians consuming biofortified cassava and maize varieties. The evidence on the nutritional impact, consumer and farmer acceptance, and cost-effective scalability of biofortified crops documented by the program resulted in the integration of biofortified crops in several key national public policies and social protection programs; private seed and food company products/investments, as well as in humanitarian aid.

Dynamic activity in cis-regulatory elements of leukocytes identifies transcription factor activation and stratifies COVID-19 severity in ICU patients.

Transcription factor programs mediating the immune response to coronavirus disease 2019 (COVID-19) are not fully understood. Capturing active transcription initiation from cis-regulatory elements such as enhancers and promoters by capped small RNA sequencing (csRNA-seq), in contrast to capturing steady-state transcripts by conventional RNA-seq, allows unbiased identification of the underlying transcription factor activity and regulatory pathways. Here, we profile transcription initiation in critically ill COVID-19 patients, identifying transcription factor motifs that correlate with clinical lung injury and disease severity. Unbiased clustering reveals distinct subsets of cis-regulatory elements that delineate the cell type, pathway-specific, and combinatorial transcription factor activity. We find evidence of critical roles of regulatory networks, showing that STAT/BCL6 and E2F/MYB regulatory programs from myeloid cell populations are activated in patients with poor disease outcomes and associated with COVID-19 susceptibility genetic variants. More broadly, we demonstrate how capturing acute, disease-mediated changes in transcription initiation can provide insight into the underlying molecular mechanisms and stratify patient disease severity.