Effect of a 2-week interruption in methotrexate treatment on COVID-19 vaccine response in people with immune-mediated inflammatory diseases (VROOM study): a randomised, open label, superiority trial.

BACKGROUND: Methotrexate is the first-line treatment for immune-mediated inflammatory diseases and reduces vaccine-induced immunity. We evaluated if a 2-week interruption of methotrexate treatment immediately after COVID-19 booster vaccination improved antibody response against the S1 receptor binding domain (S1-RBD) of the SARS-CoV-2 spike protein and live SARS-CoV-2 neutralisation compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases. METHOD: We did a multicentre, open-label, parallel-group, randomised, superiority trial in secondary-care rheumatology and dermatology clinics in 26 hospitals in the UK. Adults (aged ≥18 years) with immune-mediated inflammatory diseases taking methotrexate (≤25 mg per week) for at least 3 months, who had received two primary vaccine doses from the UK COVID-19 vaccination programme were eligible. Participants were randomly assigned (1:1) using a centralised validated computer program, to temporarily suspend methotrexate treatment for 2 weeks immediately after COVID-19 booster vaccination or continue treatment as usual. The primary outcome was S1-RBD antibody titres 4 weeks after COVID-19 booster vaccination and was assessed masked to group assignment. All randomly assigned patients were included in primary and safety analyses. This trial is registered with ISRCTN, ISRCTN11442263; following a pre-planned interim analysis, recruitment was stopped early. FINDING: Between Sept 30, 2021, and March 7, 2022, we screened 685 individuals, of whom 383 were randomly assigned: to either suspend methotrexate (n=191; mean age 58·8 years [SD 12·5], 118 [62%] women and 73 [38%] men) or to continue methotrexate (n=192; mean age 59·3 years [11·9], 117 [61%] women and 75 [39%] men). At 4 weeks, the geometric mean S1-RBD antibody titre was 25 413 U/mL (95% CI 22 227-29 056) in the suspend methotrexate group and 12 326 U/mL (10 538-14 418) in the continue methotrexate group with a geometric mean ratio (GMR) of 2·08 (95% CI 1·59-2·70; p<0·0001). No intervention-related serious adverse events occurred. INTERPRETATION: 2-week interruption of methotrexate treatment in people with immune-mediated inflammatory diseases enhanced antibody responses after COVID-19 booster vaccination that were sustained at 12 weeks and 26 weeks. There was a temporary increase in inflammatory disease flares, mostly self-managed. The choice to suspend methotrexate should be individualised based on disease status and vulnerability to severe outcomes from COVID-19. FUNDING: National Institute for Health and Care Research.

Development of Expert-Level Classification of Seizures and Rhythmic and Periodic Patterns During EEG Interpretation.

BACKGROUND AND OBJECTIVES: Seizures (SZs) and other SZ-like patterns of brain activity can harm the brain and contribute to in-hospital death, particularly when prolonged. However, experts qualified to interpret EEG data are scarce. Prior attempts to automate this task have been limited by small or inadequately labeled samples and have not convincingly demonstrated generalizable expert-level performance. There exists a critical unmet need for an automated method to classify SZs and other SZ-like events with expert-level reliability. This study was conducted to develop and validate a computer algorithm that matches the reliability and accuracy of experts in identifying SZs and SZ-like events, known as "ictal-interictal-injury continuum" (IIIC) patterns on EEG, including SZs, lateralized and generalized periodic discharges (LPD, GPD), and lateralized and generalized rhythmic delta activity (LRDA, GRDA), and in differentiating these patterns from non-IIIC patterns. METHODS: We used 6,095 scalp EEGs from 2,711 patients with and without IIIC events to train a deep neural network, SPaRCNet, to perform IIIC event classification. Independent training and test data sets were generated from 50,697 EEG segments, independently annotated by 20 fellowship-trained neurophysiologists. We assessed whether SPaRCNet performs at or above the sensitivity, specificity, precision, and calibration of fellowship-trained neurophysiologists for identifying IIIC events. Statistical performance was assessed by the calibration index and by the percentage of experts whose operating points were below the model's receiver operating characteristic curves (ROCs) and precision recall curves (PRCs) for the 6 pattern classes. RESULTS: SPaRCNet matches or exceeds most experts in classifying IIIC events based on both calibration and discrimination metrics. For SZ, LPD, GPD, LRDA, GRDA, and "other" classes, SPaRCNet exceeds the following percentages of 20 experts-ROC: 45%, 20%, 50%, 75%, 55%, and 40%; PRC: 50%, 35%, 50%, 90%, 70%, and 45%; and calibration: 95%, 100%, 95%, 100%, 100%, and 80%, respectively. DISCUSSION: SPaRCNet is the first algorithm to match expert performance in detecting SZs and other SZ-like events in a representative sample of EEGs. With further development, SPaRCNet may thus be a valuable tool for an expedited review of EEGs. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among patients with epilepsy or critical illness undergoing EEG monitoring, SPaRCNet can differentiate (IIIC) patterns from non-IIIC events and expert neurophysiologists.

Interrater Reliability of Expert Electroencephalographers Identifying Seizures and Rhythmic and Periodic Patterns in EEGs.

BACKGROUND AND OBJECTIVES: The validity of brain monitoring using electroencephalography (EEG), particularly to guide care in patients with acute or critical illness, requires that experts can reliably identify seizures and other potentially harmful rhythmic and periodic brain activity, collectively referred to as "ictal-interictal-injury continuum" (IIIC). Previous interrater reliability (IRR) studies are limited by small samples and selection bias. This study was conducted to assess the reliability of experts in identifying IIIC. METHODS: This prospective analysis included 30 experts with subspecialty clinical neurophysiology training from 18 institutions. Experts independently scored varying numbers of ten-second EEG segments as "seizure (SZ)," "lateralized periodic discharges (LPDs)," "generalized periodic discharges (GPDs)," "lateralized rhythmic delta activity (LRDA)," "generalized rhythmic delta activity (GRDA)," or "other." EEGs were performed for clinical indications at Massachusetts General Hospital between 2006 and 2020. Primary outcome measures were pairwise IRR (average percent agreement [PA] between pairs of experts) and majority IRR (average PA with group consensus) for each class and beyond chance agreement (κ). Secondary outcomes were calibration of expert scoring to group consensus, and latent trait analysis to investigate contributions of bias and noise to scoring variability. RESULTS: Among 2,711 EEGs, 49% were from women, and the median (IQR) age was 55 (41) years. In total, experts scored 50,697 EEG segments; the median [range] number scored by each expert was 6,287.5 [1,002, 45,267]. Overall pairwise IRR was moderate (PA 52%, κ 42%), and majority IRR was substantial (PA 65%, κ 61%). Noise-bias analysis demonstrated that a single underlying receiver operating curve can account for most variation in experts' false-positive vs true-positive characteristics (median [range] of variance explained ([Formula: see text]): 95 [93, 98]%) and for most variation in experts' precision vs sensitivity characteristics ([Formula: see text]: 75 [59, 89]%). Thus, variation between experts is mostly attributable not to differences in expertise but rather to variation in decision thresholds. DISCUSSION: Our results provide precise estimates of expert reliability from a large and diverse sample and a parsimonious theory to explain the origin of disagreements between experts. The results also establish a standard for how well an automated IIIC classifier must perform to match experts. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that an independent expert review reliably identifies ictal-interictal injury continuum patterns on EEG compared with expert consensus.

Compositional Aspects of Beverages Designed to Promote Hydration Before, During, and After Exercise: Concepts Revisited.

Hypohydration can impair aerobic performance and deteriorate cognitive function during exercise. To minimize hypohydration, athletes are recommended to commence exercise at least euhydrated, ingest fluids containing sodium during long-duration and/or high-intensity exercise to prevent body mass loss over 2% and maintain elevated plasma osmolality, and rapidly restore and retain fluid and electrolyte homeostasis before a second exercise session. To achieve these goals, the compositions of the fluids consumed are key; however, it remains unclear what can be considered an optimal formulation for a hydration beverage in different settings. While carbohydrate-electrolyte solutions such as sports drinks have been extensively explored as a source of carbohydrates to meet fuel demands during intense and long-duration exercise, these formulas might not be ideal in situations where fluid and electrolyte balance is impaired, such as practicing exercise in the heat. Alternately, hypotonic compositions consisting of moderate to high levels of electrolytes (i.e., ≥45 mmol/L), mainly sodium, combined with low amounts of carbohydrates (i.e., <6%) might be useful to accelerate intestinal water absorption, maintain plasma volume and osmolality during exercise, and improve fluid retention during recovery. Future studies should compare hypotonic formulas and sports drinks in different exercise settings, evaluating different levels of sodium and/or other electrolytes, blends of carbohydrates, and novel ingredients for addressing hydration and rehydration before, during, and after exercise.

Hormone replacement therapy (conjugated oestrogens plus bazedoxifene) for post-menopausal women with symptomatic hand osteoarthritis: primary report from the HOPE-e randomised, placebo-controlled, feasibility study.

Background: Symptomatic hand osteoarthritis is more common in women than in men, and its incidence increases around the age of menopause, implicating oestrogen deficiency. No randomised controlled trials of hormone replacement therapy (HRT) have been done in people with hand osteoarthritis. We aimed to determine the feasibility and acceptability of a form of HRT (conjugated oestrogens plus bazedoxifene) in post-menopausal women with painful hand osteoarthritis. Methods: The HOPE-e feasibility study was a randomised, double-blind, placebo-controlled trial, for which we recruited women aged 40-65 years, for whom 1-10 years had passed after their final menstrual period, with definite hand osteoarthritis and at least two painful hand joints. Participants were recruited across three primary or secondary care sites and from the community and were randomly assigned (1:1) to receive conjugated oestrogens plus bazedoxifene or placebo, orally once every day for 24 weeks, before weaning for 4 weeks until the end of the study. The primary feasibility outcomes were rates of identification, recruitment, randomisation, retention, and compliance of eligible participants, and the likelihood of unmasking. The secondary objective was to generate proof-of-concept quantitative and qualitative data on the acceptability of proposed clinical outcomes for a full trial and adverse events. We used an intention-to-treat analysis, and criteria for progression to a full trial were pre-defined as recruitment of at least 30 participants across all sites in 18 months; a dropout rate of less than or equal to 30% of randomised individuals; and acceptability to the majority of participants, including acceptable rates of adverse events. Due to the COVID-19 pandemic, the recruitment window was reduced to 12-15 months. A proportionately reduced minimum sample size of 22 was judged to be sufficient to test feasibility. This trial was registered at ISRCTN, ISRCTN12196200. Findings: From May 9, 2019 to Dec 31, 2020, 434 enquiries or referrals were received. We did 96 telephone pre-screens; of the 35 eligible participants, seven were excluded as ineligible at the telephone or face-to-face screening and 28 (80% [95% CI 63-92]) were randomly assigned. Of the 406 who were not randomly assigned, 250 (62%) were ineligible (with contraindicated medications accounting for 50 [20%] of these), 101 (25%) did not respond to further enquiries, and 55 (14%) chose not to proceed (with the most common reason being not wanting to take a hormone-based drug). All 28 randomised participants completed all follow-up assessments with high compliance and outcome measure completeness. All three adverse event-related treatment withdrawals were in the placebo group. No serious adverse events were reported. Participants and investigators were successfully masked (participant Bang's blinding index placebo group 0·50 [95% CI 0·25-0·75]). The trial met the prespecified criteria for progression to a full trial. Interpretation: This first-ever feasibility study of a randomised controlled trial of HRT for post-menopausal women with painful hand osteoarthritis met its progression criteria, although it was not powered to detect a clinical effect. This outcome indicates that a full trial of an HRT in this population is feasible and acceptable and identifies potential refinements with regard to the design of such a trial. Funding: Research for Patient Benefit programme, National Institute for Health Research.

Support from Work and Intent to Stay Among Nurses During COVID-19: An Academic-Practice Collaboration.

The COVID-19 pandemic created stressful working conditions for nurses and challenges for leaders. A survey was conducted among 399 acute and ambulatory care nurses measuring availability of calming and safety resources, perceptions of support from work, and intent to stay. Most nurses reported intent to stay with their employer, despite inadequate safety and calming resources. High levels of support from work were significantly influenced nurses' intent to stay. Leadership actions at the study site to provide support are described, providing context for results. Nurse leaders can positively influence intent to stay through consistent implementation of supportive measures.

Hand Osteoarthritis: investigating Pain Effects of estrogen-containing therapy (HOPE-e): a protocol for a feasibility randomised placebo-controlled trial.

BACKGROUND: Hand osteoarthritis (OA) is a common condition, causing pain, stiffness and reduced quality of life. Incidence is higher amongst women, particularly around the age of the menopause. Whilst the relationship between sex hormones and OA has been studied in vitro, in epidemiological studies and in clinical trials of hormone replacement therapy (HRT), this study is the first to investigate the effect of estrogen-containing therapy on hand pain in post-menopausal women with symptomatic hand OA in a randomised study design. METHODS: This is a feasibility study of a double-blinded placebo-controlled intervention with 1:1 randomisation to either a combination of conjugated estrogens 0.45 mg and bazedoxifene acetate 20 mg (Duavive) or placebo. The target population is post-menopausal women with symptomatic hand OA, aiming to recruit 60-90 study participants. The primary objective is to assess the feasibility of a future fully powered randomised controlled trial (RCT). Participants will take the study medication for 24 weeks and be followed up for 28 weeks after randomisation. The primary outcomes used to determine feasibility are eligible participant identification rates and routes; recruitment, randomisation and retention rates of eligible participants; study medication compliance; and the likelihood of unintentional unblinding. Secondary outcomes include measures of hand pain, function, appearance and menopausal symptoms. An end of study questionnaire and focus groups will help to refine the final protocol for a full study. DISCUSSION: Identifying new treatments for symptomatic hand OA is a recognised research priority. The study will help us to understand whether there are sufficient interested and eligible individuals in this target population who would consider HRT for their hand symptoms. It will provide proof-of-concept RCT data on the effects of HRT on hand pain and other clinically relevant outcomes in this population. The study will gain valuable information on the feasibility of a full RCT and how best to run this. The findings will be published in a peer-reviewed journal and presented at a relevant conference. TRIAL REGISTRATION: ISRCTN12196200 registered on 15 January 2019.

Utilization of Current Diagnostic Indicators to Characterize Pediatric Undernutrition among US Children.

The purpose of this study was to estimate the prevalence of pediatric undernutrition in the US general population using the Academy of Nutrition and Dietetics/American Society for Parenteral and Enteral Nutrition consensus statement on identification of pediatric malnutrition (undernutrition). National Health and Nutrition Examination Survey (NHANES) data for years 2005-2014 was analyzed for children ages 1-13 years (n = 13,950) with valid anthropometric data. The prevalence of undernutrition was assessed through z-scores for weight-for-height, body mass index (BMI)-for-age, height-for-age, and mid-upper-arm circumference-for-age generated from the 2000 Centers for Disease Control and Prevention growth charts. Children were stratified into: no undernutrition, mild undernutrition, and moderate or severe undernutrition. Descriptive statistics were used to identify the prevalence of undernutrition. Differences in Z-scores across growth chart metrics were compared across undernutrition categories using analysis of variance. The total prevalence of pediatric undernutrition in this sample was 0.4% (severe undernutrition), 2.0% (moderate undernutrition), and 10.9% (mild undernutrition) for all ages. Z-scores differed significantly across all levels of undernutrition for all anthropometrics, showing poorer mean growth metrics in those with undernutrition. Pediatric undernutrition is a prevalent condition that transcends the prior focus on <5th percentile of growth curves and impacts children across different demographic categories.

Smartphone EEG and remote online interpretation for children with epilepsy in the Republic of Guinea: Quality, characteristics, and practice implications.

PURPOSE: Children with epilepsy in low-income countries often go undiagnosed and untreated. We examine a portable, low-cost smartphone-based EEG technology in a heterogeneous pediatric epilepsy cohort in the West African Republic of Guinea. METHODS: Children with epilepsy were recruited at the Ignace Deen Hospital in Conakry, 2017. Participants underwent sequential EEG recordings with an app-based EEG, the Smartphone Brain Scanner-2 (SBS2) and a standard Xltek EEG. Raw EEG data were transmitted via Bluetooth™ connection to an Android™ tablet and uploaded for remote EEG specialist review and reporting via a new, secure web-based reading platform, crowdEEG. The results were compared to same-visit Xltek 10-20 EEG recordings for identification of epileptiform and non-epileptiform abnormalities. RESULTS: 97 children meeting the International League Against Epilepsy's definition of epilepsy (49 male; mean age 10.3 years, 29 untreated with an antiepileptic drug; 0 with a prior EEG) were enrolled. Epileptiform discharges were detected on 21 (25.3%) SBS2 and 31 (37.3%) standard EEG recordings. The SBS2 had a sensitivity of 51.6% (95%CI 32.4%, 70.8%) and a specificity of 90.4% (95%CI 81.4%, 94.4%) for all types of epileptiform discharges, with positive and negative predictive values of 76.2% and 75.8% respectively. For generalized discharges, the SBS2 had a sensitivity of 43.5% with a specificity of 96.2%. CONCLUSIONS: The SBS2 has a moderate sensitivity and high specificity for the detection of epileptiform abnormalities in children with epilepsy in this low-income setting. Use of the SBS2+crowdEEG platform permits specialist input for patients with previously poor access to clinical neurophysiology expertise.

Seizures in HIV: The case for special consideration.

PURPOSE: This study aimed to determine the rate, cause and management of seizures in the context of potential ART-ASD interactions in a cohort of HIV + individuals. METHODS: Records of 604 HIV + patients were reviewed and those reporting epilepsy/seizure diagnosis were further evaluated. RESULTS: This cohort exhibited a seizure rate of 2.4%. HIV + patients treated for epilepsy displayed low serum ASD levels and failed to achieve seizure control. They were more likely to disengage from Neurology follow-up. CONCLUSION: For HIV + patients presenting with seizures/epilepsy the ASD prescription and the provision of supplementary support services needs to be carefully considered.

Aciclovir-induced acute kidney injury in patients with 'suspected viral encephalitis' encountered on a liaison neurology service.

BACKGROUND: Patients with 'suspected viral encephalitis' are frequently empirically treated with intravenous aciclovir. Increasing urea and creatinine are 'common', but rapidly progressive renal failure is reported to be 'very rare'. AIMS: To describe the clinical course and outcome of cases of aciclovir-induced acute kidney injury (AKI) encountered by the Liaison Neurology Service at AMNCH and to highlight the importance of surveillance and urgent treatment of this iatrogenic complication. METHODS: Retrospectively and prospectively collected data from the Liaison Neurology Service at AMNCH on patients who received IV aciclovir for suspected viral encephalitis and developed AKI were analysed. Aciclovir-induced AKI was defined by a consultant nephrologist in all cases as a rise in serum creatinine of > 26 µmol/L in 48 h or by ≥ 1.5 times the baseline value. Renal function, haematocrit, and fluid balance were monitored following AKI onset. RESULTS: Data from 10 patients were analysed. Median time to AKI onset was 3.5 days (range: 1-6 days). Aciclovir was stopped or the dose adjusted. All patients recovered with IV normal saline, aiming for a urine output > 100-150 ml/h. The interval between first rise in creatinine and return to normal levels varied between 5 and 19 days. CONCLUSIONS: Liaison neurologists and general physicians need to be aware that aciclovir may cause AKI attributed to distal intra-tubular crystal nephropathy. Daily fluid balance and renal function monitoring are essential because AKI may arise even with intensive pre-hydration. Prognosis is good if identified early and actively treated.

Mono- and diglycerides improve lutein absorption in healthy adults: a randomised, double-blind, cross-over, single-dose study.

With the association between increased carotenoid intake and lower risk of chronic diseases, the absorption of lutein from the diet becomes an important factor in its delivery and physiological action. The primary objective of this study was to gain an understanding of how a new formulation technology (mixture of mono- and diglycerides (MDG)), affected lutein absorption. Subjects (n 24) were randomised in a cross-over, double-blind study to receive a single dose of 6 mg lutein (FloraGLO 20 %) provided as capsules containing either high-oleic safflower (SAF) oil or a MDG oil. Subjects receiving a single dose of lutein in MDG showed a significantly greater change from baseline (0 h) to 4, 6, 8, 12, 24, 48 and 336 h (P<0·05) and baseline adjusted AUC for plasma lutein at 48 and 336 h (P<0·001) as compared with subjects given lutein in SAF. Analysis of the 48 h absorption kinetics of lutein showed that the time to peak level of lutein (12 h) was the same for SAF and MDG groups, but the change in plasma lutein at 12 and 48 h were 129 and 320 % higher, respectively, for MDG compared with SAF. This difference continued as the adjusted AUC 0-48 and 0-336 h for the MDG group was 232 and 900 % higher, respectively, v. SAF. The study data show that by changing the lipid that is combined with a lutein supplement results in significant increases in lutein absorption in healthy adults.

An exploration of the spectrum of peri-ictal MRI change; a comprehensive literature review.

PURPOSE: The aim of this review was to identify published studies in the literature relating to ictal induced MRI change and to identify certain common themes, practical points for clinicians and areas for future research. METHODS: We identified 96 articles that satisfied our inclusion criteria yielding 575 cases. All articles were analysed; number of subjects, spectrum of MRI and EEG change, aetiology, and follow-up (both clinical and imaging) were noted. RESULTS: The most frequent imaging changes were restricted diffusion, T2-hyperintensity and reduced ADC values. The mesial temporal structures and neocortex were most commonly affected locations though subcortical structures like the thalamus and pulvinar were also described. Practical clinical points included; the development of PLEDS concordant with ictal imaging change was associated with worse clinical prognosis, patients with seizures due to symptomatic aetiology may be more likely to develop ictal related imaging change and follow up is vitally important to ensure that ictal related oedema is not misidentified as a mass lesion or conversely that a mass lesion is not misidentified as ictal related change. CONCLUSION: Qualitative MRI studies have provided clinicians with useful in-vivo insights into the dynamic ictal neuronal environment. Changes are not only localised to the ictal focus but can be remote and irreversible. Small patient numbers varying study design and high numbers of symptomatic seizures makes comparison between studies problematic. Also there is possible microstructural quantitative MRI changes that are missed on qualitative MRI. There is a need for prospective quantitative MRI studies in patients with epilepsy peri-icatlly with a uniform period of follow up and comparison to control data.

Forecasting behavior in smart homes based on sleep and wake patterns.

BACKGROUND: The goal of this research is to use smart home technology to assist people who are recovering from injuries or coping with disabilities to live independently. OBJECTIVE: We introduce an algorithm to model and forecast wake and sleep behaviors that are exhibited by the participant. Furthermore, we propose that sleep behavior is impacted by and can be modeled from wake behavior, and vice versa. METHODS: This paper describes the Behavior Forecasting (BF) algorithm. BF consists of 1) defining numeric values that reflect sleep and wake behavior, 2) forecasting wake and sleep values from past behavior, 3) analyzing the effect of wake behavior on sleep and vice versa, and 4) improving prediction performance by using both wake and sleep scores. RESULTS: The BF method was evaluated with data collected from 20 smart homes. We found that regardless of the forecasting method utilized, wake behavior and sleep behavior can be modeled with a minimum accuracy of 84%. Additionally, normalizing the wake and sleep scores drastically improves the accuracy to 99%. CONCLUSIONS: The results show that we can effectively model wake and sleep behaviors in a smart environment. Furthermore, wake behaviors can be predicted from sleep behaviors and vice versa.

Regulation of C3 Activation by the Alternative Complement Pathway in the Mouse Retina.

The purpose of this study was to examine the retinas of mice carrying hemizygous and null double deletions of Cfb-/- and Cfh-/-, and to compare these with the single knockouts of Cfb, Cfh and Cfd. Retinas were isolated from wild type (WT), Cfb-/-/Cfh-/-, Cfb-/-/Cfh+/-, Cfh-/-/Cfb+/-, Cfb-/-, Cfh-/- Cfd-/-, and Cfd+/- mice. Complement proteins were evaluated by western blotting, ELISA and immunocytochemistry, and retinal morphology was assessed using toluidine blue stained semi-thin sections. WT mice showed staining for C3 and its breakdown products in the retinal vasculature and the basal surface of the retinal pigment epithelium (RPE). Cfb-/- mice exhibited a similar C3 staining pattern to WT in the retinal vessels but a decrease in C3 and its breakdown products at the basal surface of the RPE. Deletion of both Cfb and Cfh restored C3 to levels similar to those observed in WT mice, however this reversal of phenotype was not observed in Cfh-/-/Cfb+/- or Cfb-/-/Cfh+/- mice. Loss of CFD caused an increase in C3 and a decrease in C3 breakdown products along the basal surface of the RPE. Overall the retinal morphology and retinal vasculature did not appear different across the various genotypes. We observed that C3 accumulates at the basal RPE in Cfb-/-, Cfb-/-/Cfh-/-, Cfb-/-/Cfh+/-, Cfd-/- and WT mice, but is absent in Cfh-/- and Cfh-/-/Cfb+/- mice, consistent with its consumption in the serum of mice lacking CFH when CFB is present. C3 breakdown products along the surface of the RPE were either decreased or absent when CFB, CFH or CFD was deleted or partially deleted.

High Podocalyxin levels promote cell viability partially through up-regulation of Annexin A2.

Podocalyxin (PODXL) is a highly glycosylated and sialylated transmembrane protein that is up-regulated in various types of tumors and whose expression levels positively correlate with tumor grade. We previously found Podxl to be highly expressed in murine tumorigenic neural stem/progenitor cells (NSPs). Here we investigated the effects of elevated Podxl levels in these cells. NSPs overexpressing Podxl did not form brain tumors upon intracranial transplantations, indicating that high levels of this gene alone are not sufficient for tumor initiation. However, Podxl overexpression had a positive effect on cell number, sphere formation and cell viability, indicating that it might in this way contribute to the development and/or maintenance of tumors. Proteome analyses of Podxl-overexpressing and control NSPs revealed increased levels of Annexin A2 (ANXA2). We also found increased transcript levels, indicating that PODXL stimulates expression of the Anxa2 gene. Lack of Anxa2 in Podxl-overexpressing NSPs resulted in reduced viability of these cells, suggesting that PODXL-mediated pro-survival effects can at least in part be explained by increased ANXA2 levels. Finally, our data indicate that Podxl overexpression activates the MAP kinase (MAPK) pathway which in turn up-regulates Anxa2 expression. Our data indicate a novel molecular connection between PODXL and ANXA2: both exert pro-survival effects in NSPs, and PODXL positively regulates ANXA2 expression through the MAPK pathway.

Identification of diabetes, heart disease, hypertension and stroke in mid- and older-aged women: Comparing self-report and administrative hospital data records.

AIM: To estimate the prevalence of diabetes, heart disease, hypertension and stroke in self-report and hospital data in two cohorts of women; measure sensitivity and agreement between data sources; and compare between cohorts. METHODS: Women born between 1946-1951 and 1921-1926 who participated in the Australian Longitudinal Study on Women's Health (ALSWH); were New South Wales residents; and admitted to hospital (2004-2008) were included in the present study. The prevalence of diabetes, heart disease, hypertension and stroke was estimated using self-report (case 1 at latest survey, case 2 across multiple surveys) and hospital records. Agreement (kappa) and sensitivity (%) were calculated. Logistic regression measured the association between patient characteristics and agreement. RESULTS: Hypertension had the highest prevalence and estimates were higher for older women: 32.5% case 1, 45.4% case 2, 12.8% in hospital data (1946-1951 cohort); 57.8% case 1, 73.2% case 2, 38.2% in hospital data (1921-1926 cohort). Agreement was substantial for diabetes: κ = 0.75 case 1, κ = 0.70 case 2 (1946-1951 cohort); κ = 0.77 case 1, κ = 0.80 case 2 (1921-1926 cohort), and lower for other conditions. The 1946-1951 cohort had 2.08 times the odds of agreement for hypertension (95% CI 1.56 to 2.78; P < 0.0001), and 6.25 times the odds of agreement for heart disease (95% CI 4.35 to 10.0; P < 0.0001), compared with the 1921-1926 cohort. CONCLUSION: Substantial agreement was found for diabetes, indicating accuracy of ascertainment using self-report or hospital data. Self-report data appears to be less accurate for heart disease and stroke. Hypertension was underestimated in hospital data. These findings have implications for epidemiological studies relying on self-report or administrative data.

The impact of teach-back on comprehension of discharge instructions and satisfaction among emergency patients with limited health literacy: A randomized, controlled study.

OBJECTIVE: Recommended as a 'universal precaution' for improving provider-patient communication, teach-back has a limited evidence base. Discharge from the emergency department (ED) to home is an important high-risk transition of care with potential for miscommunication of critical information. We examined whether teach-back improves: comprehension and perceived comprehension of discharge instructions and satisfaction among patients with limited health literacy (LHL) in the ED. METHODS: We performed a randomized, controlled study among adult patients with LHL, to teach-back or standard discharge instructions. Patients completed an audio-recorded structured interview evaluating comprehension and perceived comprehension of (1) diagnosis, (2) ED course, (3) post-ED care, and (4) reasons to return and satisfaction using four Consumer Assessment of Healthcare Providers and Systems questions. Concordance with the medical record was rated using a five-level scale. We analyzed differences between groups using multivariable ordinal logistic regression. RESULTS: Patients randomized to receive teach-back had higher comprehension of post-ED care areas: post-ED medication (P < 0.02), self-care (P < 0.03), and follow-up instructions (P < 0.0001), but no change in patient satisfaction or perceived comprehension. CONCLUSION: Teach-back appears to improve comprehension of post-ED care instructions but not satisfaction or perceived comprehension. Our data from a randomized, controlled study support the effectiveness of teach-back in a busy clinical setting. Further research is needed to test the utility and feasibility of teach-back for routine use including its impacts on distal outcomes.

Neuropsychological test selection for cognitive impairment classification: A machine learning approach.

INTRODUCTION: Reducing the amount of testing required to accurately detect cognitive impairment is clinically relevant. The aim of this research was to determine the fewest number of clinical measures required to accurately classify participants as healthy older adult, mild cognitive impairment (MCI), or dementia using a suite of classification techniques. METHOD: Two variable selection machine learning models (i.e., naive Bayes, decision tree), a logistic regression, and two participant datasets (i.e., clinical diagnosis; Clinical Dementia Rating, CDR) were explored. Participants classified using clinical diagnosis criteria included 52 individuals with dementia, 97 with MCI, and 161 cognitively healthy older adults. Participants classified using CDR included 154 individuals with CDR = 0, 93 individuals with CDR = 0.5, and 25 individuals with CDR = 1.0+. A total of 27 demographic, psychological, and neuropsychological variables were available for variable selection. RESULTS: No significant difference was observed between naive Bayes, decision tree, and logistic regression models for classification of both clinical diagnosis and CDR datasets. Participant classification (70.0-99.1%), geometric mean (60.9-98.1%), sensitivity (44.2-100%), and specificity (52.7-100%) were generally satisfactory. Unsurprisingly, the MCI/CDR = 0.5 participant group was the most challenging to classify. Through variable selection only 2-9 variables were required for classification and varied between datasets in a clinically meaningful way. CONCLUSIONS: The current study results reveal that machine learning techniques can accurately classify cognitive impairment and reduce the number of measures required for diagnosis.

A pilot study to assess the utility and perceived effectiveness of a tool for diagnosing feeding difficulties in children.

BACKGROUND: Food dislikes in children may result in avoiding particular food/s with major sources of essential nutrients leading to increased risk of impaired growth or cognitive development and compromised immune function. It is necessary to identify conditions contributing to feeding difficulty and associated complications. An instrument was designed to assist diagnosis and management of children with feeding difficulties. The study was conducted to test utility of the "Identification and Management of Feeding Difficulties (IMFeD)" tool in Indian children. METHODS: A prospective, cross-sectional study was conducted in Indian children between 2 and 10 years identified to have picky eating behaviour. After completion of both pro forma sections (parent and physician) of the IMFeD tool, the child's specific feeding difficulty was diagnosed and appropriate nutritional and/or behavioural counselling was provided. The subjects were followed at 30 and 60 days post-intervention. RESULTS: According to 66% of paediatricians the IMFeD tool was very easy to use. Approximately 85% of paediatricians required ≤20 min to administer the tool, diagnose the feeding difficulty(ies) and provide specific counselling or behavioural management. More than 70% of parents were satisfied and willing to accept the use of the IMFeD tool. After 60 days, 65% of the parents were either less worried or not worried at all about the feeding behaviour of the child using recommendations made on the basis of the IMFeD tool. The toolkit helped parents to know what to do if their child had a feeding problem. A total of 90% of the parents expressed that the tool is useful for assessing feeding difficulties in children. CONCLUSION: The IMFeD tool can be effectively used to identify feeding difficulties in Indian children. This toolkit also helps to offer nutritional and behavioural guidance as a part of the management.