Deciphering the Interplay between the Epithelial Barrier, Immune Cells, and Metabolic Mediators in Allergic Disease.

Chronic exposure to harmful pollutants, chemicals, and pathogens from the environment can lead to pathological changes in the epithelial barrier, which increase the risk of developing an allergy. During allergic inflammation, epithelial cells send proinflammatory signals to group 2 innate lymphoid cell (ILC2s) and eosinophils, which require energy and resources to mediate their activation, cytokine/chemokine secretion, and mobilization of other cells. This review aims to provide an overview of the metabolic regulation in allergic asthma, atopic dermatitis (AD), and allergic rhinitis (AR), highlighting its underlying mechanisms and phenotypes, and the potential metabolic regulatory roles of eosinophils and ILC2s. Eosinophils and ILC2s regulate allergic inflammation through lipid mediators, particularly cysteinyl leukotrienes (CysLTs) and prostaglandins (PGs). Arachidonic acid (AA)-derived metabolites and Sphinosine-1-phosphate (S1P) are significant metabolic markers that indicate immune dysfunction and epithelial barrier dysfunction in allergy. Notably, eosinophils are promoters of allergic symptoms and exhibit greater metabolic plasticity compared to ILC2s, directly involved in promoting allergic symptoms. Our findings suggest that metabolomic analysis provides insights into the complex interactions between immune cells, epithelial cells, and environmental factors. Potential therapeutic targets have been highlighted to further understand the metabolic regulation of eosinophils and ILC2s in allergy. Future research in metabolomics can facilitate the development of novel diagnostics and therapeutics for future application.

Directed Evolution of Acoustic Reporter Genes Using High-Throughput Acoustic Screening.

A major challenge in the fields of biological imaging and synthetic biology is noninvasively visualizing the functions of natural and engineered cells inside opaque samples such as living animals. One promising technology that addresses this limitation is ultrasound (US), with its penetration depth of several cm and spatial resolution on the order of 100 µm. Within the past decade, reporter genes for US have been introduced and engineered to link cellular functions to US signals via heterologous expression in commensal bacteria and mammalian cells. These acoustic reporter genes (ARGs) represent a novel class of genetically encoded US contrast agent, and are based on air-filled protein nanostructures called gas vesicles (GVs). Just as the discovery of fluorescent proteins was followed by the improvement and diversification of their optical properties through directed evolution, here we describe the evolution of GVs as acoustic reporters. To accomplish this task, we establish high-throughput, semiautomated acoustic screening of ARGs in bacterial cultures and use it to screen mutant libraries for variants with increased nonlinear US scattering. Starting with scanning site saturation libraries for two homologues of the primary GV structural protein, GvpA/B, two rounds of evolution resulted in GV variants with 5- and 14-fold stronger acoustic signals than the parent proteins. We anticipate that this and similar approaches will help high-throughput protein engineering play as large a role in the development of acoustic biomolecules as it has for their fluorescent counterparts.

Meteorin-like protein/METRNL/Interleukin-41 ameliorates atopic dermatitis-like inflammation.

BACKGROUND: Meteorin-like protein (METRNL)/Interleukin-41 (IL-41) is a novel immune-secreted cytokine/myokine involved in several inflammatory diseases. However, how METRNL exerts its regulatory properties on skin inflammation remains elusive. This study aims to elucidate the functionality and regulatory mechanism of METRNL in atopic dermatitis (AD). METHODS: METRNL levels were determined in skin and serum samples from patients with AD and subsequently verified in the vitamin D3 analogue MC903-induced AD-like mice model. The cellular target of METRNL activity was identified by multiplex immunostaining, single-cell RNA-seq and RNA-seq. RESULTS: METRNL was significantly upregulated in lesions and serum of patients with dermatitis compared to healthy controls (p <.05). Following repeated MC903 exposure, AD model mice displayed elevated levels of METRNL in both ears and serum. Administration of recombinant murine METRNL protein (rmMETRNL) ameliorated allergic skin inflammation and hallmarks of AD in mice, whereas blocking of METRNL signaling led to the opposite. METRNL enhanced ß-Catenin activation, limited the expression of Th2-related molecules that attract the accumulation of Arginase-1 (Arg1)hi macrophages, dendritic cells, and activated mast cells. CONCLUSIONS: METRNL can bind to KIT receptor and subsequently alleviate the allergic inflammation of AD by inhibiting the expansion of immune cells, and downregulating inflammatory gene expression by regulating the level of active WNT pathway molecule ß-Catenin.

Directed Evolution of Acoustic Reporter Genes Using High-Throughput Acoustic Screening.

A major challenge in the fields of biological imaging and synthetic biology is noninvasively visualizing the functions of natural and engineered cells inside opaque samples such as living animals. One promising technology that addresses this limitation is ultrasound (US), with its penetration depth of several cm and spatial resolution on the order of 100 µm. 1 Within the past decade, reporter genes for US have been introduced 2,3 and engineered 4,5 to link cellular functions to US signals via heterologous expression in commensal bacteria and mammalian cells. These acoustic reporter genes (ARGs) represent a novel class of genetically encoded US contrast agent, and are based on air-filled protein nanostructures called gas vesicles (GVs). 6 Just as the discovery of fluorescent proteins was followed by the improvement and diversification of their optical properties through directed evolution, here we describe the evolution of GVs as acoustic reporters. To accomplish this task, we establish high-throughput, semi-automated acoustic screening of ARGs in bacterial cultures and use it to screen mutant libraries for variants with increased nonlinear US scattering. Starting with scanning site saturation libraries for two homologs of the primary GV structural protein, GvpA/B, two rounds of evolution resulted in GV variants with 5- and 14-fold stronger acoustic signals than the parent proteins. We anticipate that this and similar approaches will help high-throughput protein engineering play as large a role in the development of acoustic biomolecules as it has for their fluorescent counterparts.

Effects of rare kidney diseases on kidney failure: a longitudinal analysis of the UK National Registry of Rare Kidney Diseases (RaDaR) cohort.

BACKGROUND: Individuals with rare kidney diseases account for 5-10% of people with chronic kidney disease, but constitute more than 25% of patients receiving kidney replacement therapy. The National Registry of Rare Kidney Diseases (RaDaR) gathers longitudinal data from patients with these conditions, which we used to study disease progression and outcomes of death and kidney failure. METHODS: People aged 0-96 years living with 28 types of rare kidney diseases were recruited from 108 UK renal care facilities. The primary outcomes were cumulative incidence of mortality and kidney failure in individuals with rare kidney diseases, which were calculated and compared with that of unselected patients with chronic kidney disease. Cumulative incidence and Kaplan-Meier survival estimates were calculated for the following outcomes: median age at kidney failure; median age at death; time from start of dialysis to death; and time from diagnosis to estimated glomerular filtration rate (eGFR) thresholds, allowing calculation of time from last eGFR of 75 mL/min per 1·73 m2 or more to first eGFR of less than 30 mL/min per 1·73 m2 (the therapeutic trial window). FINDINGS: Between Jan 18, 2010, and July 25, 2022, 27 285 participants were recruited to RaDaR. Median follow-up time from diagnosis was 9·6 years (IQR 5·9-16·7). RaDaR participants had significantly higher 5-year cumulative incidence of kidney failure than 2·81 million UK patients with all-cause chronic kidney disease (28% vs 1%; p<0·0001), but better survival rates (standardised mortality ratio 0·42 [95% CI 0·32-0·52]; p<0·0001). Median age at kidney failure, median age at death, time from start of dialysis to death, time from diagnosis to eGFR thresholds, and therapeutic trial window all varied substantially between rare diseases. INTERPRETATION: Patients with rare kidney diseases differ from the general population of individuals with chronic kidney disease: they have higher 5-year rates of kidney failure but higher survival than other patients with chronic kidney disease stages 3-5, and so are over-represented in the cohort of patients requiring kidney replacement therapy. Addressing unmet therapeutic need for patients with rare kidney diseases could have a large beneficial effect on long-term kidney replacement therapy demand. FUNDING: RaDaR is funded by the Medical Research Council, Kidney Research UK, Kidney Care UK, and the Polycystic Kidney Disease Charity.

Dark under the Lamp: Neglected Biological Pollutants in the Environment Are Closely Linked to Lung Cancer.

Environmental pollutants are closely linked to lung cancer. The different types of environmental pollutants can be classified as chemical, physical, and biological. The roles of common chemical and physical pollutants such as PM2.5, smoking, radon, asbestos, and formaldehyde in lung cancer have been extensively studied. Notably, the worldwide COVID-19 pandemic raised awareness of the strong link between biological pollution and human health. Allergens such as house dust mites and pollen, as well as bacteria and viruses, are common biological pollutants. A few biological pollutants have been reported to promote lung cancer via inducing inflammatory cytokines secretion, such as IL-1ß, IL-6, and TGF-ß, as well as suppressing immunosurveillance by upregulating regulatory T (Treg) cells while dampening the function of CD8+ T cells and dendritic cells. However, the correlation between common biological hazards, such as SARS-CoV-2, human immunodeficiency viruses, Helicobacter pylori, and house dust mites, and lung cancer is not fully elucidated, and the underlying mechanisms are still unclear. Moreover, the majority of studies that have been performed in lung cancer and biological carcinogens were not based on the perspective of biological pollutants, which has challenged the systematicity and coherence in the field of biological pollutants in lung cancer. Here, in addition to reviewing the recent progress made in investigating the roles of allergens, viruses, and bacteria in lung cancer, we summarized the potential mechanisms underlying biological pollutants in lung cancer. Our narrative review can shed light on understanding the significance of biological pollutants in lung cancer, as well as inspire and broaden research ideas on lung cancer etiology.

Long-Term Outcomes in IgA Nephropathy.

BACKGROUND: IgA nephropathy can progress to kidney failure, and risk assessment soon after diagnosis has advantages both for clinical management and the development of new therapeutics. We present relationships among proteinuria, eGFR slope, and lifetime risks for kidney failure. METHODS: The IgA nephropathy cohort (2299 adults and 140 children) of the UK National Registry of Rare Kidney Diseases (RaDaR) was analyzed. Patients enrolled had a biopsy-proven diagnosis of IgA nephropathy plus proteinuria >0.5 g/d or eGFR <60 ml/min per 1.73 m 2 . Incident and prevalent populations and a population representative of a typical phase 3 clinical trial cohort were studied. Analyses of kidney survival were conducted using Kaplan-Meier and Cox regression. eGFR slope was estimated using linear mixed models with random intercept and slope. RESULTS: The median (Q1, Q3) follow-up was 5.9 (3.0, 10.5) years; 50% of patients reached kidney failure or died in the study period. The median (95% confidence interval [CI]) kidney survival was 11.4 (10.5 to 12.5) years; the mean age at kidney failure/death was 48 years, and most patients progressed to kidney failure within 10-15 years. On the basis of eGFR and age at diagnosis, almost all patients were at risk of progression to kidney failure within their expected lifetime unless a rate of eGFR loss ≤1 ml/min per 1.73 m 2 per year was maintained. Time-averaged proteinuria was significantly associated with worse kidney survival and more rapid eGFR loss in incident, prevalent, and clinical trial populations. Thirty percent of patients with time-averaged proteinuria of 0.44 to <0.88 g/g and approximately 20% of patients with time-averaged proteinuria <0.44 g/g developed kidney failure within 10 years. In the clinical trial population, each 10% decrease in time-averaged proteinuria from baseline was associated with a hazard ratio (95% CI) for kidney failure/death of 0.89 (0.87 to 0.92). CONCLUSIONS: Outcomes in this large IgA nephropathy cohort are generally poor with few patients expected to avoid kidney failure in their lifetime. Significantly, patients traditionally regarded as being low risk, with proteinuria <0.88 g/g (<100 mg/mmol), had high rates of kidney failure within 10 years.

Characterization of METRNß as a novel biomarker of Coronavirus disease 2019 severity and prognosis.

Introduction: Coronavirus disease 2019 (COVID-19) is increasing worldwide, with complications due to frequent viral mutations, an intricate pathophysiology, and variable host immune responses. Biomarkers with predictive and prognostic value are crucial but lacking. Methods: Serum samples from authentic and D614G variant (non-Omicron), and Omicron-SARS-CoV-2 infected patients were collected for METRNß detection and longitudinal cytokine/chemokine analysis. Correlation analyses were performed to compare the relationships between serum METRNß levels and cytokines/chemokines, laboratory parameters, and disease severity. Receiver operating characteristic (ROC) curves and Kaplan-Meier survival curves were used to evaluate the predictive value of METRNß in COVID-19. Results: The serum level of METRNß was highly elevated in non-Omicron-SARS-CoV-2 infected patients compared to healthy individuals, and the non-survivor displayed higher METRNß levels than survivors among the critical ones. METRNß concentration showed positive correlation with viral load in NAPS. ROC curve showed that a baseline METRNß level of 1886.89 pg/ml distinguished COVID-19 patients from non-infected individuals with an AUC of 0.830. Longitudinal analysis of cytokine/chemokine profiles revealed a positive correlation between METRNß and pro-inflammatory cytokines such as IL6, and an inverse correlation with soluble CD40L (sCD40L). Higher METRNß was associated with increased mortality. These findings were validated in a second and third cohort of COVID-19 patients identified in a subsequent wave. Discussion: Our study uncovered the precise role of METRNß in predicting the severity of COVID-19, thus providing a scientific basis for further evaluation of the role of METRNß in triage therapeutic strategies.

Genomically mined acoustic reporter genes for real-time in vivo monitoring of tumors and tumor-homing bacteria.

Ultrasound allows imaging at a much greater depth than optical methods, but existing genetically encoded acoustic reporters for in vivo cellular imaging have been limited by poor sensitivity, specificity and in vivo expression. Here we describe two acoustic reporter genes (ARGs)-one for use in bacteria and one for use in mammalian cells-identified through a phylogenetic screen of candidate gas vesicle gene clusters from diverse bacteria and archaea that provide stronger ultrasound contrast, produce non-linear signals distinguishable from background tissue and have stable long-term expression. Compared to their first-generation counterparts, these improved bacterial and mammalian ARGs produce 9-fold and 38-fold stronger non-linear contrast, respectively. Using these new ARGs, we non-invasively imaged in situ tumor colonization and gene expression in tumor-homing therapeutic bacteria, tracked the progression of tumor gene expression and growth in a mouse model of breast cancer, and performed gene-expression-guided needle biopsies of a genetically mosaic tumor, demonstrating non-invasive access to dynamic biological processes at centimeter depth.

The experiences of UK-Chinese individuals during the COVID-19 pandemic: A qualitative interview study.

Infectious disease outbreaks have historically been associated with stigmatisation towards minority groups, specifically those associated with the geographical region that the disease was first identified. We aimed to investigate how the emerging COVID-19 pandemic was experienced by UK-resident individuals of Chinese ethnicity: how their perceived cultural and ethnic identity influenced their experiences, and how early insights into the pandemic in China influenced attitudes and behaviours. We undertook in-depth semi-structured interviews with individuals who self-identified as UK-Chinese. Participants were recruited from three cities in the UK. Interviews were undertaken over the telephone between 9th April 2020 and 16th July 2020. Interviews were digitally recorded and transcribed verbatim. Transcripts were coded using NVivo software and analysed using inductive thematic analysis. Sixteen individuals were interviewed. Three main themes were identified: (1) Attribution of stigma, (2) Pandemic legacies, and (3) Individual versus societal responses. These reflected six sub-themes: (1) Stigmatisation through (mis)identity, (2) Markers of pandemic awareness, (3) Legacies of previous pandemics, (4) Ascription of blame, (5) Extent of freedom, and (6) Implicit faith in government. Experiences of xenophobia included accounts of physical violence. UK-Chinese individuals experienced and perceived widespread xenophobia, in the context of media representations that ascribed blame and exacerbated stigmatisation. Prior experience of respiratory epidemics, and insight into the governmental and societal response in China, contributed to the early adoption of face masks. This in turn marked UK-Chinese individuals as targets for abuse. Awareness is needed to safeguard stigmatized groups from social and economic harm in future infectious disease pandemics.

The UK Chinese population with kidney failure: Clinical characteristics, management and access to kidney transplantation using 20 years of UK Renal Registry and NHS Blood and Transplant data.

BACKGROUND: Little is known about the clinical demographics of and access to transplantation for Chinese diaspora populations with kidney disease. METHODS: The UK Renal Registry provided data on adults with ethnicity recorded as 'Chinese' or 'White' starting Kidney Replacement Therapy (KRT) 1/1/97-31/12/17. Baseline characteristics were compared between Chinese and White patients. Multivariable logistic regression models were used to investigate the relationships between Chinese ethnicity and i) being listed for deceased-donor transplantation at start of KRT, ii) being listed 2 years after start of KRT, iii) pre-emptive kidney transplantation, iv) kidney transplantation 3 years after start of KRT, and v) living-donor kidney transplantation (LDKT). RESULTS: UK Chinese patients were younger at start of KRT (61.6 vs 65.6 years, p <0.001) and had more diabetic kidney disease (29% vs 20%, p<0.001) and glomerulonephritis (21% vs 13%, p<0.001) than White patients. We found evidence of interaction between ethnicity and sex. Compared to UK White men, UK Chinese men had lower odds of pre-emptive transplant (aOR 0.28, 95% CI [0.10-0.76]) and transplant within 3 years of KRT start (aOR 0.65, [95% CI 0.49-0.87], P = 0.004). UK White women and Chinese women had the same likelihood of pre-emptive transplant (aOR 0.78, 95% CI [0.38-1.61]), or transplant within 3 years of KRT start (aOR 0.94, 95% CI [0.60-1.46]). Both UK Chinese men and women had markedly lower odds of LDKT compared to Whites aOR 0.34 [95% CI 0.21-0.53]. CONCLUSIONS: UK Chinese are less likely to receive a LDKT. UK Chinese men have lower odds of accessing pre-emptive wait-listing and transplantation. Understanding whether these disparities reflect modifiable barriers will help ensure equitable access to transplantation.

Attachment styles moderate Theory of Mind differences between persons with schizophrenia, first-degree relatives and controls.

OBJECTIVES: Theory of Mind (ToM) plays a role in social functioning and is impaired in patients with schizophrenia and to a lesser degree in first-degree relatives, compared to healthy controls. This study investigates whether attachment styles moderate these observed group differences in ToM. METHODS: This cross-sectional study included a sample of 51 patients, 23 first-degree relatives, and 49 controls who completed assessments of anxious and avoidant attachment (Psychosis Attachment Measure), ToM (Reading the Mind in the Eyes Test), and estimated cognitive ability. Patients' symptoms were assessed with the Positive and Negative Syndrome Scale. RESULTS: Patients differed from controls and relatives in ToM performance but not in attachment avoidance or attachment anxiety. Attachment anxiety showed an interaction with group over ToM. The interaction was significant only between patients and controls but not between patients and relatives or relatives and controls. Post-hoc analysis showed that patients and controls showed differential ToM performance at average and high attachment anxiety. In patients, symptom levels did not moderate the association between attachment and ToM. CONCLUSIONS: Attachment anxiety is related to poorer levels of ToM in patients, suggesting this may have a contributory role in schizophrenia. The findings stress the need for longitudinal research into the directionality of the relationship between ToM and attachment anxiety. PRACTITIONER POINTS: Relationships with significant others might be a factor that influences the way in which social information is processed by persons with a diagnosis of a psychotic disorder. In patients, higher levels of attachment anxiety - that is, low self-worth, fear of abandonment and rejection, continuous vigilance of threat-related cues - were associated with a lower ability to understand the mental states of others. However, at lower levels of attachment anxiety, their ToM performance was comparable to that of relatives and controls. This effect was not influenced by symptom severity. Further research is required to confirm the potential influence of attachment insecurity on ToM ability as the latter is strongly related to patient's functional outcomes.

Cognitive performance in early, treatment-resistant psychosis patients: Could cognitive control play a role in persistent symptoms?

Approximately one third of psychosis patients fail to respond to conventional antipsychotic medication, which exerts its effect via striatal dopamine receptor antagonism. The present study aimed to investigate impaired cognitive control as a potential contributor to persistent positive symptoms in treatment resistant (TR) patients. 52 medicated First Episode Psychosis (FEP) patients (17 TR and 35 non-TR (NTR)) took part in a longitudinal study in which they performed a series of cognitive tasks and a clinical assessment at two timepoints, 12 months apart. Cognitive performance at baseline was compared to that of 39 healthy controls (HC). Across both timepoints, TR patients were significantly more impaired than NTR patients in a task of cognitive control, while performance on tasks of phonological and semantic fluency, working memory and general intelligence did not differ between patient groups. No significant associations were found between cognitive performance and psychotic symptomatology, and no significant performance changes were observed from the first to second timepoint in any of the cognitive tasks within patient groups. The results suggest that compared with NTR patients, TR patients have an exacerbated deficit specific to cognitive control, which is established early in psychotic illness and stabilises in the years following a first episode.

Investigating Ethnic Disparity in Living-Donor Kidney Transplantation in the UK: Patient-Identified Reasons for Non-Donation among Family Members.

There is ethnic inequity in access to living-donor kidney transplants in the UK. This study asked kidney patients from Black, Asian and minority ethnic groups why members of their family were not able to be living kidney donors. Responses were compared with responses from White individuals. This questionnaire-based mixed-methods study included adults transplanted between 1/4/13-31/3/17 at 14 UK hospitals. Participants were asked to indicate why relatives could not donate, selecting all options applicable from: Age; Health; Weight; Location; Financial/Cost; Job; Blood group; No-one to care for them after donation. A box entitled 'Other-please give details' was provided for free-text entries. Multivariable logistic regression was used to analyse the association between the likelihood of selecting each reason for non-donation and the participant's self-reported ethnicity. Qualitative responses were analysed using inductive thematic analysis. In total, 1240 questionnaires were returned (40% response). There was strong evidence that Black, Asian and minority ethnic group individuals were more likely than White people to indicate that family members lived too far away to donate (adjusted odds ratio (aOR) = 3.25, 95% Confidence Interval (CI) 2.30-4.58), were prevented from donating by financial concerns (aOR = 2.95, 95% CI 2.02-4.29), were unable to take time off work (aOR = 1.88, 95% CI 1.18-3.02), were "not the right blood group" (aOR = 1.65, 95% CI 1.35-2.01), or had no-one to care for them post-donation (aOR = 3.73, 95% CI 2.60-5.35). Four qualitative themes were identified from responses from Black, Asian and minority ethnic group participants: 'Burden of disease within the family'; 'Differing religious interpretations'; 'Geographical concerns'; and 'A culture of silence'. Patients perceive barriers to living kidney donation in the UK Black, Asian and minority ethnic population. If confirmed, these could be targeted by interventions to redress the observed ethnic inequity.

Has the UK living kidney donor population changed over time? A cross-sectional descriptive analysis of the UK living donor registry between 2006 and 2017.

BACKGROUND: A living-donor kidney transplant is the best treatment for most people with kidney failure. Population cohort studies have shown that lifetime living kidney donor risk is modified by sex, age, ethnicity, body mass index (BMI), comorbidity and relationship to the recipient. OBJECTIVES: We investigated whether the UK population of living kidney donors has changed over time, investigating changes in donor demographics. DESIGN: We undertook a cross-sectional analysis of the UK living kidney donor registry between January 2006 to December 2017. Data were available on living donor sex, age, ethnicity, BMI, hypertension and relationship to recipient. SETTING: UK living donor registry. PARTICIPANTS: 11 651 consecutive living kidney donors from January 2006 to December 2017. OUTCOME MEASURES: Living kidney donor demographic characteristics (sex, age, ethnicity, BMI and relationship to the transplant recipient) were compared across years of donation activity. Donor characteristics were also compared across different ethnic groups. RESULTS: Over the study period, the mean age of donors increased (from 45.8 to 48.7 years, p<0.001), but this change appears to have been limited to the White population of donors. Black donors were younger than White donors, and a greater proportion were siblings of their intended recipient and male. The proportion of non-genetically related non-partner donations increased over the 12-year period of analysis (p value for linear trend=0.002). CONCLUSIONS: The increasing age of white living kidney donors in the UK has implications for recipient and donor outcomes. Despite an increase in the number of black, Asian and minority ethnic individuals waitlisted for a kidney transplant, there has been no increase in the ethnic diversity of UK living kidney donors. Black donors in the UK may be at a much greater risk of developing kidney failure due to accumulated risks: whether these risks are being communicated needs to be investigated.

Restrictive Transfusion Practice in Adults Receiving Venovenous Extracorporeal Membrane Oxygenation: A Single-Center Experience.

OBJECTIVES: Restrictive transfusion policies have been adopted in critical care, although these have not included patients receiving extracorporeal membrane oxygenation. We aimed to assess survival outcomes, adverse events related to RBC transfusion, and cost implications following a change from a "liberal" to a "restrictive" RBC transfusion practice in patients receiving extracorporeal membrane oxygenation. DESIGN: Retrospective observational study. SETTING: Single high-volume tertiary critical care department at a university hospital. PATIENTS: Patients 16 years old or greater receiving venovenous extracorporeal membrane oxygenation between 2011 and 2017 for more than 24 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical diagnoses, complications, outcomes, median hemoglobin, and hematocrit levels were obtained from patients' electronic records. All laboratory results for hemoglobin and hematocrit were included. RBC transfusions were obtained from prescription charts. We included 402 patients: 99 during a "liberal" transfusion practice (2011-2014)-when the target hemoglobin level was greater than 100 g/L; and 303 treated during a "restrictive" transfusion practice (2014-2017) when the target hemoglobin level was greater than 80 g/L. We found that survival outcomes did not change following the implementation of a "restrictive" transfusion policy. There was also a decrease in the extracorporeal blood flow rates with restrictive transfusion of 0.5 L/min. Nonsurvivors of venovenous extracorporeal membrane oxygenation had higher usage of RBC units following a change in transfusion practice. The restrictive strategy allowed a cost saving of £454 per patient. CONCLUSIONS: These results suggest that the adoption of a more restrictive approach to RBC transfusion during venovenous extracorporeal membrane oxygenation is more cost-effective and associated with similar survival outcomes, than when compared with a more liberal approach.

Neural correlates of positive and negative symptoms through the illness course: an fMRI study in early psychosis and chronic schizophrenia.

Psychotic illness is associated with cognitive control deficits and abnormal recruitment of neural circuits subserving cognitive control. It is unclear to what extent this dysfunction underlies the development and/or maintenance of positive and negative symptoms typically observed in schizophrenia. In this study we compared fMRI activation on a standard Stroop task and its relationship with positive and negative symptoms in early psychosis (EP, N = 88) and chronic schizophrenia (CHR-SZ, N = 38) patients. CHR-SZ patients showed reduced frontal, striatal, and parietal activation across incongruent and congruent trials compared to EP patients. Higher positive symptom severity was associated with reduced activation across both trial types in supplementary motor area (SMA), middle temporal gyrus and cerebellum in EP, but not CHR-SZ patients. Higher negative symptom severity was associated with reduced cerebellar activation in EP, but not in CHR-SZ patients. A negative correlation between negative symptoms and activation in SMA and precentral gyrus was observed in EP patients and in CHR-SZ patients. The results suggest that the neural substrate of positive symptoms changes with illness chronicity, and that cognitive control related neural circuits may be most relevant in the initial development phase of positive symptoms. These findings also highlight a changing role for the cerebellum in the development and later maintenance of both positive and negative symptoms.

Cognitive correlates of abnormal myelination in psychosis.

Psychotic illness has consistently been associated with deficits in cognitive function and reduced white matter integrity in the brain. However, the link between white matter disruptions and deficits in cognitive domains remains poorly understood. We assessed cognitive performance and white matter myelin water fraction (MWF) using multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) in recent-onset psychosis patients and age-matched healthy controls (HC). Psychosis patients showed deficits in working memory, phonological and semantic fluency, general intelligence quotient and reduced MWF in the left temporal white matter compared to HC. MWF in the left inferior fronto-occipital fasciculus and inferior longitudinal fasciculus was positively associated with intelligence quotient and verbal fluency in patients, and fully mediated group differences in performance in both phonological and semantic verbal fluency. There was no association between working memory and MWF in the left temporal white matter. Negative symptoms demonstrated a negative association with MWF within the left inferior and superior longitudinal fasciculi. These findings indicate that psychosis-related deficits in distinct cognitive domains, such as verbal fluency and working memory, are not underpinned by a single common dysfunction in white matter connectivity.

Functional recovery following critical illness in children: the "wee-cover" pilot study.

OBJECTIVE: To determine the feasibility of conducting a longitudinal prospective study to evaluate functional recovery and predictors of impaired functional recovery in critically ill children. DESIGN: Prospective pilot study. SETTING: Single-center PICU at McMaster Children's Hospital, Hamilton, Canada. PATIENTS: Children aged 12 months to 17 years, with at least one organ dysfunction, limited mobility or bed rest during the first 48 hours of PICU admission, and a minimum 48-hour PICU length of stay, were eligible. Patients transferred from a neonatal ICU prior to ever being discharged home, already mobilizing well or at baseline functional status at time of screening, with an English language barrier, and prior enrollment into this study, were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was feasibility, as defined by the ability to screen, enroll eligible patients, and execute the study procedures and measurements on participants. Secondary outcomes included functional status at baseline, 3 and 6 months, PICU morbidity, and mortality. Functional status was measured using the Pediatric Evaluation of Disability Inventory and the Participation and Environment Measure for Children and Youth. Thirty-three patients were enrolled between October 2012 and April 2013. Consent rate was 85%, and follow-up rates were 93% at 3 months and 71% at 6 months. We were able to execute the study procedures and measurements, demonstrating feasibility of conducting a future longitudinal study. Functional status deteriorated following critical illness. Recovery appears to be influenced by baseline health or functional status and severity of illness. CONCLUSION: Longitudinal research is needed to understand how children recover after a critical illness. Our results suggest factors that may influence the recovery trajectory and were used to inform the methodology, outcomes of interest, and appropriate sample size of a larger multicenter study evaluating functional recovery in this population.

Private primary care physicians' perspectives on factors affecting the adoption of electronic medical records: a qualitative pre-implementation study.

BACKGROUND: Use of electronic medical records (EMR) has the potential to offer quality and safety benefits, but without the adoption of the technology, the benefits will not be realized. OBJECTIVE: This study aimed to identify the factors perceived as relevant by private physicians when considering EMR adoption. METHODS: A qualitative pre-implementation study was conducted using semi-structured, face to face interviews to explore the perspectives of physicians (n=16) operating in private clinics on the factors affecting their adoption of EMR. A multilevel, work system approach and the immersion/crystallization data analysis technique guided the researchers in examining the data, identifying patterns and key themes, and extracting representative quotes to illustrate these themes. RESULTS: The major factors associated with EMR adoption, which relate to the five categories of a work system, were system usefulness; user interface design; technical support; cost; system reliability; the privacy, confidentiality, and security of patient information; physical space in the clinic; data migration process; adverse work-related factors; and the computer and systems skills of physicians. CONCLUSIONS: Pre-implementation identification of factors important to adoption can allow system developers to focus proactively on these factors when developing the system and its implementation strategies, to maximize the likelihood of successful introduction.