Identification of Idiopathic Pulmonary Fibrosis and Prediction of Disease Severity via Machine Learning Analysis of Comprehensive Metabolic Panel and Complete Blood Count Data.

BACKGROUND: Diagnosis of idiopathic pulmonary fibrosis (IPF) typically relies on high-resolution computed tomography imaging (HRCT) or histopathology, while monitoring disease severity is done via frequent pulmonary function testing (PFT). More reliable and convenient methods of diagnosing fibrotic interstitial lung disease (ILD) type and monitoring severity would allow for early identification and enhance current therapeutic interventions. This study tested the hypothesis that a machine learning (ML) ensemble analysis of comprehensive metabolic panel (CMP) and complete blood count (CBC) data can accurately distinguish IPF from connective tissue disease ILD (CTD-ILD) and predict disease severity as seen with PFT. METHODS: Outpatient data with diagnosis of IPF or CTD-ILD (n = 103 visits by 53 patients) were analyzed via ML methodology to evaluate (1) IPF vs CTD-ILD diagnosis; (2) %predicted Diffusing Capacity of Lung for Carbon Monoxide (DLCO) moderate or mild vs severe; (3) %predicted Forced Vital Capacity (FVC) moderate or mild vs severe; and (4) %predicted FVC mild vs moderate or severe. RESULTS: ML methodology identified IPF from CTD-ILD with AUCTEST = 0.893, while PFT was classified as DLCO moderate or mild vs severe with AUCTEST = 0.749, FVC moderate or mild vs severe with AUCTEST = 0.741, and FVC mild vs moderate or severe with AUCTEST = 0.739. Key features included albumin, alanine transaminase, %lymphocytes, hemoglobin, %eosinophils, white blood cell count, %monocytes, and %neutrophils. CONCLUSION: Analysis of CMP and CBC data via proposed ML methodology offers the potential to distinguish IPF from CTD-ILD and predict severity on associated PFT with accuracy that meets or exceeds current clinical practice.

Chronic activation of adrenal Gq signaling induces Cyp11b2 expression in the zona fasciculata and hyperaldosteronism.

Hyperaldosteronism is often associated with inappropriate aldosterone production and aldosterone synthase (Cyp11b2) expression. Normally, Cyp11b2 expression is limited to the adrenal zona glomerulosa (ZG) and regulated by angiotensin II which signals through Gq protein-coupled receptors. As cells migrate inwards, they differentiate into 11ß-hydroxylase-expressing zona fasciculata (ZF) cells lacking Cyp11b2. The mechanism causing ZG-specific aldosterone biosynthesis is still unclear. We investigated the effect of chronic Gq signaling using transgenic mice with a clozapine N-oxide (CNO)-activated human M3 muscarinic receptor (DREADD) coupled to Gq (hM3Dq) that was expressed throughout the adrenal cortex. CNO raised circulating aldosterone in the presence of a high sodium diet with greater response seen in females compared to males. Immunohistochemistry and transcriptomics indicated disrupted zonal Cyp11b2 expression while Wnt signaling remained unchanged. Chronic Gq-DREADD signaling also induced an intra-adrenal RAAS in CNO-treated mice. Chronic Gq signaling disrupted adrenal cortex zonal aldosterone production associated with ZF expression of Cyp11b2.

Disease diagnosis and severity classification in pulmonary fibrosis using carbonyl volatile organic compounds in exhaled breath.

BACKGROUND: Pathophysiological conditions underlying pulmonary fibrosis remain poorly understood. Exhaled breath volatile organic compounds (VOCs) have shown promise for lung disease diagnosis and classification. In particular, carbonyls are a byproduct of oxidative stress, associated with fibrosis in the lungs. To explore the potential of exhaled carbonyl VOCs to reflect underlying pathophysiological conditions in pulmonary fibrosis, this proof-of-concept study tested the hypothesis that volatile and low abundance carbonyl compounds could be linked to diagnosis and associated disease severity. METHODS: Exhaled breath samples were collected from outpatients with a diagnosis of Idiopathic Pulmonary Fibrosis (IPF) or Connective Tissue related Interstitial Lung Disease (CTD-ILD) with stable lung function for 3 months before enrollment, as measured by pulmonary function testing (PFT) DLCO (%), FVC (%) and FEV1 (%). A novel microreactor was used to capture carbonyl compounds in the breath as direct output products. A machine learning workflow was implemented with the captured carbonyl compounds as input features for classification of diagnosis and disease severity based on PFT (DLCO and FVC normal/mild vs. moderate/severe; FEV1 normal/mild/moderate vs. moderately severe/severe). RESULTS: The proposed approach classified diagnosis with AUROC=0.877 ± 0.047 in the validation subsets. The AUROC was 0.820 ± 0.064, 0.898 ± 0.040, and 0.873 ± 0.051 for disease severity based on DLCO, FEV1, and FVC measurements, respectively. Eleven key carbonyl VOCs were identified with the potential to differentiate diagnosis and to classify severity. CONCLUSIONS: Exhaled breath carbonyl compounds can be linked to pulmonary function and fibrotic ILD diagnosis, moving towards improved pathophysiological understanding of pulmonary fibrosis.

The utility of community-based participatory research: Increasing research engagement among minoritized ethnoracial groups.

OBJECTIVE: This article conceptually examined the need for and utility of community-based participatory research (CBPR) approaches for increasing rates of engagement in psychological research among underserved minoritized ethnoracial groups. METHODS: This article examined the literature for relevant studies examining rates of research engagement by minoritized ethnoracial groups, significant factors precluding research engagement, and the consequences of this disparity for mental health outcomes. The theoretical literature outlining the development and utility of alternative, community-based participatory research methods was included. Key features of CBPR were examined along with limitations of current approaches. A case study example of CBPR is provided. RESULTS: The use of CBPR approaches has been documented to improve health outcomes, reduce stigma toward mental health research and treatment, and build the professional capacity of community partners, particularly among minoritized ethnoracial groups. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: CBPR engagement practices are a means of reducing the mental health research gap for ethnic and racial minoritized groups. The use of such approaches in future research and practice will directly inform how existing psychological treatments may be modified per the needs of the patient, address long standing issues of cultural mistrust toward professional institutions, and reduce mental health stigma in underserved communities. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Biomechanics of wheelchair turning manoeuvres: novel insights into wheelchair propulsion.

Introduction: Wheelchair turning biomechanics is an under researched area despite its obvious relevance to functional mobility of wheelchair users. Wheelchair turns might be linked to a higher risk of upper limb injuries due to the increased forces and torques potentially associated with asymmetric movement. Our aim was to obtain a better theoretical understanding of wheelchair turning by biomechanically analyzing turns compared to steady-state straightforward propulsion (SSSFP). Methods: Ten able-bodied men received 12-min familiarization and 10 trials (in a random order) of SSSFP and multiple left and right turns around a rectangular course. A Smartwheel was mounted at the right wheel of a standard wheelchair to measure kinetic parameters during SSSFP and of the inner hand during right turns and the outer hand during left turns. A repeated measures ANOVA was used to detect differences across tasks. Results: Two strategies were identified: 3% demonstrated roll turns and 97% spin turns. Spin turns consisted of three phases: approach, turning and depart phase. The turning phase was accomplished by increasing peak force (72.9 ± 25.1 N vs. 43.38 ± 15.9 N in SSSFP) of the inner hand, while maintaining high push frequency of the outer hand (1.09 ± 0.20 push/s vs. 0.95 ± 0.13 push/s in SSSFP). Peak negative force and force impulse during the turning phase were much higher than SSSFP, 15.3 ± 15.7 and 4.5 ± 1.7 times higher, respectively. Conclusion: The spin turn strategy might carry an increased risk of upper limb injuries due to higher braking force and requires particular attention by rehabilitation professionals to preserve upper limb function of long-term wheelchair users.

Inhibition of Chk2 promotes neuroprotection, axon regeneration, and functional recovery after CNS injury.

DNA double-strand breaks occur in many acute and long-term neurological conditions, including neurodegeneration, neurotrauma, and stroke. Nonrepaired breaks chronically activate the DNA damage response in neurons, leading to neural dysfunction and apoptosis. Here, we show that targeting of the central ATM-Chk2 pathway regulating the response to double-strand breaks slows neural decline in Drosophila models of chronic neurodegeneration. Inhibitors of ATM-Chk2, but not the parallel ATR-Chk1 pathway, also promote marked, functional recovery after acute central nervous system injury in rats, suggesting that inhibiting nonhomologous end-joining rather than homologous recombination is crucial for neuroprotection. We demonstrate that the Chk2 inhibitor, prexasertib, which has been evaluated in phase 2 clinical trials for cancer, has potent neuroprotective effects and represents a new treatment option to promote functional recovery after spinal cord or optic nerve injury.

Aging and skeletal muscle force control: Current perspectives and future directions.

During voluntary muscle contractions, force output is characterized by constant inherent fluctuations, which can be quantified either according to their magnitude or temporal structure, that is, complexity. The presence of such fluctuations when targeting a set force indicates that control of force is not perfectly accurate, which can have significant implications for task performance. Compared to young adults, older adults demonstrate a greater magnitude and lower complexity in force fluctuations, indicative of decreased steadiness, and adaptability of force output, respectively. The nature of this loss-of-force control depends not only on the age of the individual but also on the muscle group performing the task, the intensity and type of contraction and whether the task is performed with additional cognitive load. Importantly, this age-associated loss-of-force control is correlated with decreased performance in a range of activities of daily living and is speculated to be of greater importance for functional capacity than age-associated decreases in maximal strength. Fortunately, there is evidence that acute physical activity interventions can reverse the loss-of-force control in older individuals, though whether this translates to improved functional performance and whether lifelong physical activity can protect against the changes have yet to be established. A number of mechanisms, related to both motor unit properties and the behavior of motor unit populations, have been proposed for the age-associated changes in force fluctuations. It is likely, though, that age-associated changes in force control are related to increased common fluctuations in the discharge times of motor units.

An estrogen-sensitive fibroblast population drives abdominal muscle fibrosis in an inguinal hernia mouse model.

Greater than 25% of all men develop an inguinal hernia in their lifetime, and more than 20 million inguinal hernia repair surgeries are performed worldwide each year. The mechanisms causing abdominal muscle weakness, the formation of inguinal hernias, or their recurrence are largely unknown. We previously reported that excessively produced estrogen in the lower abdominal muscles (LAMs) triggers extensive LAM fibrosis, leading to hernia formation in a transgenic male mouse model expressing the human aromatase gene (Aromhum). To understand the cellular basis of estrogen-driven muscle fibrosis, we performed single-cell RNA sequencing on LAM tissue from Aromhum and wild-type littermates. We found a fibroblast-like cell group composed of 6 clusters, 2 of which were validated for their enrichment in Aromhum LAM tissue. One of the potentially novel hernia-associated fibroblast clusters in Aromhum was enriched for the estrogen receptor-α gene (Esr1hi). Esr1hi fibroblasts maximally expressed estrogen target genes and seemed to serve as the progenitors of another cluster expressing ECM-altering enzymes (Mmp3hi) and to upregulate expression of proinflammatory, profibrotic genes. The discovery of these 2 potentially novel and unique hernia-associated fibroblasts may lead to the development of novel treatments that can nonsurgically prevent or reverse inguinal hernias.

Retrospective Safety Evaluation of a Pharmacist-Assisted Total Dose Iron Sucrose Protocol in Hospital Inpatients With Iron Deficiency Anemia.

BACKGROUND: Intravenous (IV) iron sucrose can be used for iron deficiency anemia (IDA), but little information exists on total dose infusion (TDI) of this drug. At a tertiary hospital, an iron sucrose TDI protocol was implemented with staff pharmacists aiding physicians in appropriate dosing. OBJECTIVES: We sought to define the safety and efficacy of this protocol in adults ≥18 years old with IDA. METHODS: We conducted a retrospective chart review of patients who received iron sucrose TDI. Inclusion criteria included patients ≥18 years old who were hospitalized and received iron sucrose in doses ≥300 mg. We reviewed the medical record for adverse reactions to any TDI of iron sucrose as well as pre-TDI and post-TDI hemoglobin (Hgb) levels to assess efficacy. RESULTS: A total of 238 patients received iron sucrose TDI for IDA during the study period. One hundred ninety-three (81%) patients were female, and the mean age in our cohort was 60.6 years. Mean pre-TDI Hgb was 8.76 g/dL. The mean total dose of iron sucrose in the total cohort was 680 mg (range: 300-2500 mg). Adverse effects attributable to iron sucrose were reported in 15 patients, with nausea being the most common effect (7/238, 2.9%). When matching patients' preadmission and postadmission records, a Hgb increase of 2.1 g/L was found (P < .001). No increase in liver function tests was found in any patient. CONCLUSIONS: A pharmacist-assisted iron sucrose TDI protocol for patients with IDA successfully increased serum Hgb and was well tolerated. Anaphylaxis was not reported.

Implementation of High-Flow Nasal Cannula Therapy Outside the Intensive Care Setting.

BACKGROUND: High-flow nasal cannula (HFNC) is an option for respiratory support in patients with acute hypoxic respiratory failure. To improve patient outcomes, reduce ICU-associated costs, and ease ICU bed availability, a multi-phased, comprehensive strategy was implemented to make HFNC available outside the ICU under the supervision of pulmonology or trauma providers in cooperation with a dedicated respiratory therapy team. The purpose of this study was to describe the education and implementation process for initiating HFNC therapy outside the ICU and to convey key patient demographics and outcomes from the implementation period. METHODS: HFNC therapy was implemented at a tertiary hospital in the Midwest, with systematic roll-out to all in-patient floors over a 9-month period. Utilization of the therapy and patient outcomes were tracked to ensure safety and efficacy of the effort. RESULTS: During the implementation period, 346 unique subjects met study inclusion criteria. Median (interquartile range) hospital length of stay was 8 d (4-12), and median duration of HFNC therapy was 44 h (18-90). Two thirds of subjects (n = 238) received the entire course of HFNC therapy outside the ICU, and more than half of subjects (n = 184) avoided the ICU for their entire hospitalization. Moreover, 6% of subjects in the study group escalated from HFNC to noninvasive ventilation, and 5% of subjects escalated from HFNC to mechanical ventilation. CONCLUSIONS: A comprehensive implementation process and a robust therapy protocol were integral to initiating and managing HFNC in all hospital locations. Study findings indicate that patients with acute hypoxic respiratory failure can safely receive HFNC therapy outside the ICU with appropriate patient selection and staff education.

Standard Gamble to Derive Utility Health States for Limbal Stem Cell Deficiency.

PURPOSE: To generate UK health-related quality-of-life (HRQoL) data for adult patients with moderate-to-severe limbal stem cell deficiency (LSCD), unilateral or bilateral, due to physical or chemical ocular burns to help inform economic evaluations of treatments. PATIENTS AND METHODS: EQ-5D-3L with vision bolt-on scores was prospectively measured for one of five clinical scenarios of LSCD described in vignettes in a demographically representative population of 520 UK adults. These were converted to health state utilities using three different UK value sets. A standard gamble (SG) was then undertaken using 12 SG scenarios to examine the component drivers of health utility for the treatment of LSCD. RESULTS: For the EQ-5D-3L scenarios, the mean disutility for LSCD with poor visual acuity, pain and disfigurement in both eyes compared to one eye was -0.084 (range=-0.156 to -0.045 across the value sets). The mean disutility of bilateral LSCD with pain, disfigurement, and poor visual acuity compared to unilateral LSCD with only poor visual acuity in one eye was -0.104 (range=-0.151 to -0.078). Similarly, where one eye was affected, pain and disfigurement in combination were associated with a greater mean disutility than improvements in visual acuity alone: -0.011 (range=-0.04 to 0.005). Mean SG utilities were within a narrow range (0.682-0.765). Where one eye was affected, the main driver was disfigurement: mean utility was 0.731 (0.709-0.753) compared to 0.682 (0.659-0.704) when disfigurement was removed compared to vision restored to normal. For bilateral LSCD, mean utilities were 0.693 (0.672-0.715) for normal vision and 0.75 (0.73-0.771) when disfigurement and pain were removed. CONCLUSION: Improvements in pain and disfigurement appeared to be the main factors driving differences in health utilities associated with symptom profiles in LSCD, with improvements in visual acuity having lesser impact.

White Paper: Yoga Therapy and Pain-How Yoga Therapy Serves in Comprehensive Integrative Pain Management, and How It Can Do More.

This paper examines the role of yoga therapy in comprehensive integrative pain management (CIPM). The pain crisis is described, and how yoga therapists can contribute to its solution is explained. Yoga therapy can be an essential component of the multidisciplinary undertaking that will be required to improve patient outcomes and alter the trajectory of the global public health crisis constituted by an epidemic of poorly understood and inadequately addressed pain. Additional context and evidence are presented to document the effectiveness of yoga therapy interventions to support people living with pain. The white paper concludes by listing recommendations to providers, consumers, payers, and legislators, who together can address systemic and structural barriers to CIPM, as well as suggestions for enabling the yoga therapy profession to more fully participate in these solutions.

Determining Physical Therapists' Readiness for Integrating Yoga Therapeutics into Rehabilitation.

The positive health effects of yoga have led physical therapists (PTs) to integrate elements of the discipline into their treatments in some settings. Formal PT education includes limited, if any, training in yoga, and there is no system in place to provide education on safely implementing therapeutic yoga (TY) as an adjunctive treatment approach. The purposes of this study were to: (1) assess the readiness of PTs (those who do not currently prescribe TY to patients) to integrate TY into treatment, and (2) determine the feasibility of a 5-week online TY training to improve the readiness of PTs to utilize TY in their practices. Licensed PTs (n = 103) were recruited nationally through social media and email. Eligible and consented PTs registered for a 5-week online TY training course. PTs' perceptions of TY and the role of safety and confidence in prescribing TY to patients were measured at baseline and postintervention. Feasibility outcomes were measured after completion of the course. Benchmarks included: (1) > 70% of PTs would find the course acceptable; (2) > 60% would finish the course; and (3) there would be significant improvements in PTs' perceptions of TY. A total of 95 eligible PTs consented and registered for the course, with 60 (63.1%) completing the intervention. Prior to the training, most PTs felt they were not ready (n = 19/60, 31.7%) or somewhat ready (n = 25/60, 41.7%) to integrate TY. More than half thought the online training was acceptable (n = 50/60, 83.3%) and finished the course (n = 60/95, 63.1%). There were significant improvements in personal readiness and confidence to safely prescribe TY, current understanding/knowledge of TY, and feeling adequately trained to use some form of TY with patients. A 5-week online TY training course is feasible to deliver for improving PTs' readiness to prescribe TY. Future studies are proposed to test the effectiveness of TY training and education with PTs.

Lessons from Vienna: stakeholder perceptions of functional electrical stimulation technology and a conceptual model for practice.

Aim: Functional electrical stimulation (FES) is a technology that can be used on paralyzed muscles to allow them to move. It has been used in populations with muscle paralysis or weakness for exercise, such as spinal cord injury (SCI) and multiple sclerosis. In order to improve technology, it is vital to understand from a qualitative perspective, issues surrounding device development and implementation.Materials and Methods: In 2016, a study was conducted at the Medical University of Vienna that sought to unravel perspectives of FES exercise from the perspective of clinicians, engineers and researchers. Semi-structured, qualitative interviews were conducted on a sample of participants from the conference (n = 22). Interviews were transcribed verbatim, and text data were analysed.Results: Following this analysis, a conceptual model of FES application in the home environment was derived. We show that the likelihood of continuing FES over time may be influenced by expectations and initial education, as perceived by stakeholders.Conclusion: This model provides a tool by which researchers or clinicians may implement FES in the home environment and may assist in the increased uptake of FES exercise at home for people who may reap benefits from its use.Implications for RehabilitationFunctional electrical stimulation (FES) is a technology that enables individuals with paralysis, such as Spinal Cord Injury or Multiple Sclerosis, to exercise.Motivation and support networks, along with adequate initial education, are essential should patients be able to successfully use FES for exercise.There are unique issues associated with performing FES in the home, and compliance may be influenced by how patients perceive FES with regard to providing benefits, and what their initial expectations are.Communication and education are essential for all parties involved in the provision of FES treatment, to ensure successful treatment with FES at home.

Physical Characteristics of Youth Elite Golfers and Their Relationship With Driver Clubhead Speed.

Coughlan, D, Taylor, M, Jackson, J, Ward, N, and Beardsley, C. Physical characteristics of youth elite golfers and their relationship with driver clubhead speed. J Strength Cond Res 34(1): 212-217, 2020-Increased clubhead speed (CHS) has a strong relationship with golf performance and is related to athletic qualities in adult golfers. Research investigating the youth golfer is limited. The purpose of this study was to explore the relationships between strength and power on CHS in youth golfers. A correlational design was used to assess relationships between CHS and anthropometric, strength, and power measurements. Thirty-six male and 33 female golfers aged 13-17 took part in this study. Male golfers showed significant relationships between CHS and handicap (HCP) (r = -0.50), seated medicine ball throw to the left (SMBTL) (r = 0.67), and right (SMBTR) (r = 0.61), rotational medicine ball throw to the left (RMBTL) (r = 0.71), and right RMBTR (r = 0.62). Female golfers showed significant relationships between CHS and HCP (r = -0.52), mass (r = 0.72), countermovement jump power (r = 0.60), RMBTL (r = 0.57), RMBTR (r = 0.56). Multiple stepwise linear regression analysis identified 77% of the variance in CHS could be explained through SMBTL and RMBTL in males. In females, 84% of the variance in CHS could be explained through mass, RMBTR, and height. This study demonstrated relationships between CHS and body mass and upper-, lower-, and full-body concentric dominant power exercises. This study could aid in the development of training interventions for youth golfers.

Chemogenetic activation of adrenocortical Gq signaling causes hyperaldosteronism and disrupts functional zonation.

The mineralocorticoid aldosterone is produced in the adrenal zona glomerulosa (ZG) under the control of the renin-angiotensin II (AngII) system. Primary aldosteronism (PA) results from renin-independent production of aldosterone and is a common cause of hypertension. PA is caused by dysregulated localization of the enzyme aldosterone synthase (Cyp11b2), which is normally restricted to the ZG. Cyp11b2 transcription and aldosterone production are predominantly regulated by AngII activation of the Gq signaling pathway. Here, we report the generation of transgenic mice with Gq-coupled designer receptors exclusively activated by designer drugs (DREADDs) specifically in the adrenal cortex. We show that adrenal-wide ligand activation of Gq DREADD receptors triggered disorganization of adrenal functional zonation, with induction of Cyp11b2 in glucocorticoid-producing zona fasciculata cells. This result was consistent with increased renin-independent aldosterone production and hypertension. All parameters were reversible following termination of DREADD-mediated Gq signaling. These findings demonstrate that Gq signaling is sufficient for adrenocortical aldosterone production and implicate this pathway in the determination of zone-specific steroid production within the adrenal cortex. This transgenic mouse also provides an inducible and reversible model of hyperaldosteronism to investigate PA therapeutics and the mechanisms leading to the damaging effects of aldosterone on the cardiovascular system.

The neuronal ceroid lipofuscinosis protein Cln7 functions in the postsynaptic cell to regulate synapse development.

The neuronal ceroid lipofuscinoses (NCLs) are a group of fatal, monogenic neurodegenerative disorders with an early onset in infancy or childhood. Despite identification of the genes disrupted in each form of the disease, their normal cellular role and how their deficits lead to disease pathology is not fully understood. Cln7, a major facilitator superfamily domain-containing protein, is affected in a late infantile-onset form of NCL. Cln7 is conserved across species suggesting a common function. Here we demonstrate that Cln7 is required for the normal growth of synapses at the Drosophila larval neuromuscular junction. In a Cln7 mutant, synapses fail to develop fully leading to reduced function and behavioral changes with dysregulation of TOR activity. Cln7 expression is restricted to the post-synaptic cell and the protein localizes to vesicles immediately adjacent to the post-synaptic membrane. Our data suggest an involvement for Cln7 in regulating trans-synaptic communication necessary for normal synapse development.

Continuous tracking of startled Drosophila as an alternative to the negative geotaxis climbing assay.

The fruit fly, Drosophila, is commonly used to study late-onset neurodegenerative diseases due to the combination of powerful genetic tools, cheap and simple husbandry and short lifespan. One widely-used measure of disease progression is the age-dependent decline in motor performance that manifests in most Drosophila neurodegeneration models. This is usually quantified using a simple climbing assay. However, the standard climbing assay lacks sensitivity and suffers from high variability meaning large numbers of flies are needed or bespoke apparatus and software solutions. Here, we present a modification of the open-source, MATLAB-based, DART software to measure the decline in "startle response" with age. We demonstrate that the DART setup is more sensitive to the motor performance decline induced by adult-onset neuronal expression of amyloid beta (Aß) peptides than a traditional climbing assay despite using smaller cohorts of flies. DART also has the potential to generate multiple metrics of motor behaviour during the startle response. The software requires no coding skills to operate and the required apparatus can be purchased commercially. Therefore, DART is a more useful method than the climbing assay for longitudinal assays of motor performance and will enable higher-throughput screen for genetic and pharmacological modifiers of neurodegeneration. In our proof-of-concept screen for modifiers of Aß-dependent phenotypes, we identified that in vivo knock-down of p53 in adult neurons is neuroprotective. This supports recent work targeting p53 in vitro and demonstrates the potential for DART to be used to screen for targets that ameliorate neurodegeneration.

Apparent interference with extracorporeal membrane oxygenation by liposomal amphotericin B in a patient with disseminated blastomycosis receiving continuous renal replacement therapy.

PURPOSE: We describe the use of liposomal amphotericin B and amphotericin B deoxycholate in a critically ill patient with pulmonary blastomycosis receiving both venovenous extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT). SUMMARY: A 50-year-old African American man presented for dyspnea and cough and was noted to have blastomycosis on bronchoscopy. He developed respiratory failure and acute kidney injury, requiring mechanical ventilation, ECMO, and CRRT. After 4 days of liposomal amphotericin, the transmembrane pressure gradient on the membrane oxygenator increased dramatically without visualization of a clot, requiring a circuit exchange. A trough amphotericin B level taken the day before the exchange was undetectable for amphotericin B. After the circuit exchange, the patient was switched to amphotericin B deoxycholate. A subsequent trough level was 3.8 µg/mL. The patient improved and was able to be decannulated. However, he did require tracheostomy and long-term hemodialysis. CONCLUSION: In our case we believe that liposomal amphotericin B was significantly removed by ECMO and was responsible for the failure of the ECMO circuit. We would suggest amphotericin B deoxycholate be used in such patients preferentially and that serum levels of the drug be assessed when possible.

Applying economic models to estimate local economic benefits of improved coverage of early intervention for psychosis.

AIM: Early Intervention Psychosis Services (EIPS) for people experiencing First Episode Psychosis (FEP) offer important clinical and non-clinical benefits over standard care. Similarly, intervention for Clinical High Risk for Psychosis state (CHR-P) can prevent psychosis, ameliorate symptoms and have non-clinical benefits. This study aimed to estimate associated local economic benefits of FEP and CHR-P services compared with standard care. METHODS: Across four south London boroughs, proportion of annual number of new cases of FEP and CHR-P seen by early intervention services was estimated. Economic modelling conducted for England's mental health strategy was applied to estimate local economic impacts of current and improved service provision. RESULTS: Across four London boroughs during 2011/2012, proportion of 15-34 year olds with FEP seen by EIPS was 100.2% assuming 80/100 000 annual incidence whereas proportion with CHR-P seen by CHR-P services was 4.1% assuming 200/100 000 annual incidence. Application of economic modelling suggests that provision of EIPS to reach all new FEP cases each year would free up resources of £13.1m over 10 years including £2.0m to National Health Service (NHS) after the first year. Scaling up to reach all new CHR-P cases each year would free up resources of £19.7m over 10 years with an estimated 10-year cost of implementation gap for each 1 year cohort of £18.9m. An earlier related briefing resulted in increased funding for EIPS and new CHR-P services despite overall cuts to mental health services. CONCLUSIONS: Estimation of local economic impacts of FEP and CHR-P services was associated with improved investment in such services.