Evaluating anesthetic protocols for functional blood flow imaging in the rat eye

The purpose of this study is to evaluate the suitability of five different anesthetic protocols (isoflurane, isoflurane–xylazine, pentobarbital, ketamine–xylazine, and ketamine–xylazine–vecuronium) for functional blood flow imaging in the rat eye. Total retinal blood flow was measured at a series of time points using an ultrahigh-speed Doppler OCT system. Additionally, each anesthetic protocol was qualitatively evaluated according to the following criteria: (1) time-stability of blood flow, (2) overall rate of blood flow, (3) ocular immobilization, and (4) simplicity. We observed that different anesthetic protocols produced markedly different blood flows. Different anesthetic protocols also varied with respect to the four evaluated criteria. These findings suggest that the choice of anesthetic protocol should be carefully considered when designing and interpreting functional blood flow studies in the rat eye.United States. National Institutes of Health (R01-EY011289-29)United States. National Institutes of Health (R44-EY022864)United States. National Institutes of Health (R01-CA075289-16)United States. Air Force Office of Scientific Research (FA9550-15-1-0473)United States. Air Force Office of Scientific Research (FA9550-12-1-0499

RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis

INTRODUCTION: The lack of a standard definition for acute kidney injury has resulted in a large variation in the reported incidence and associated mortality. RIFLE, a newly developed international consensus classification for acute kidney injury, defines three grades of severity – risk (class R), injury (class I) and failure (class F) – but has not yet been evaluated in a clinical series. METHODS: We performed a retrospective cohort study, in seven intensive care units in a single tertiary care academic center, on 5,383 patients admitted during a one year period (1 July 2000–30 June 2001). RESULTS: Acute kidney injury occurred in 67% of intensive care unit admissions, with maximum RIFLE class R, class I and class F in 12%, 27% and 28%, respectively. Of the 1,510 patients (28%) that reached a level of risk, 840 (56%) progressed. Patients with maximum RIFLE class R, class I and class F had hospital mortality rates of 8.8%, 11.4% and 26.3%, respectively, compared with 5.5% for patients without acute kidney injury. Additionally, acute kidney injury (hazard ratio, 1.7; 95% confidence interval, 1.28–2.13; P < 0.001) and maximum RIFLE class I (hazard ratio, 1.4; 95% confidence interval, 1.02–1.88; P = 0.037) and class F (hazard ratio, 2.7; 95% confidence interval, 2.03–3.55; P < 0.001) were associated with hospital mortality after adjusting for multiple covariates. CONCLUSION: In this general intensive care unit population, acute kidney 'risk, injury, failure', as defined by the newly developed RIFLE classification, is associated with increased hospital mortality and resource use. Patients with RIFLE class R are indeed at high risk of progression to class I or class F. Patients with RIFLE class I or class F incur a significantly increased length of stay and an increased risk of inhospital mortality compared with those who do not progress past class R or those who never develop acute kidney injury, even after adjusting for baseline severity of illness, case mix, race, gender and age

Learning and interaction in groups with computers: when do ability and gender matter?

In the research reported in this paper, we attempt to identify the background and process factors influencing the effectiveness of groupwork with computers in terms of mathematics learning. The research used a multi-site case study design in six schools and involved eight groups of six mixed-sex, mixed-ability pupils (aged 9-12) undertaking three research tasks – two using Logo and one a database. Our findings suggest that, contrary to other recent research, the pupil characteristics of gender and ability have no direct influence on progress in group tasks with computers. However, status effects – pupils' perceptions of gender and ability – do have an effect on the functioning of the group, which in turn can impede progress for all pupils concerned

Long-Term Follow-Up After Unilateral Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy: The RESTORE Study

BACKGROUND: RESCUE and REVERSE were 2 Phase 3 clinical trials that assessed the efficacy and safety of intravitreal gene therapy with lenadogene nolparvovec (rAAV2/2-ND4) for the treatment of Leber hereditary optic neuropathy (LHON). RESTORE is the long-term follow-up study of subjects treated in the RESCUE and REVERSE trials. METHODS: In RESCUE and REVERSE, 76 subjects with LHON because of the m.11778 G&gt;A mutation in the mitochondrial gene ND4 received a single unilateral intravitreal injection of lenadogene nolparvovec. After 96 weeks, 61 subjects were enrolled in the long-term follow-up study RESTORE. The best-corrected visual acuity (BCVA) was assessed over a period of up to 52 months after onset of vision loss. A locally estimated scatterplot smoothing regression model was used to analyze changes in BCVA over time. Vision-related quality of life was reported using the visual function questionnaire-25 (VFQ-25). RESULTS: The population of MT-ND4 subjects enrolled in RESTORE was representative of the combined cohorts of RESCUE and REVERSE for mean age (35.1 years) and gender distribution (79% males). There was a progressive and sustained improvement of BCVA up to 52 months after the onset of vision loss. The final mean BCVA was 1.26 logarithm of the minimal angle of resolution 48 months after the onset of vision loss. The mean VFQ-25 composite score increased by 7 points compared with baseline. CONCLUSION: The treatment effect of lenadogene nolparvovec on BCVA and vision-related quality of life observed 96 weeks (2 years) after treatment in RESCUE and REVERSE was sustained at 3 years in RESTORE, with a maximum follow-up of 52 months (4.3 years) after the onset of vision loss

Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A ND4 Mutation: Systematic Review and Indirect Comparison

Objective: This work aimed to compare the evolution of visual outcomes in Leber hereditary optic neuropathy (LHON) patients treated with intravitreal gene therapy to the spontaneous evolution in prior natural history (NH) studies. Design: A combined analysis of two phase three randomized, double-masked, sham-controlled studies (REVERSE and RESCUE) and their joint long-term extension trial (CLIN06) evaluated the efficacy of rAAV2/2-ND4 vs. 11 pooled NH studies used as an external control. Subjects: The LHON subjects carried the m.11778G&gt;A ND4 mutation and were aged ≥15 years at onset of vision loss. Methods: A total of 76 subjects received a single intravitreal rAAV2/2-ND4 injection in one eye and sham injection in the fellow eye within 1 year after vision loss in REVERSE and RESCUE. Both eyes were considered as treated due to the rAAV2/2-ND4 treatment efficacy observed in the contralateral eyes. Best corrected visual acuity (BCVA) from REVERSE, RESCUE, and CLIN06 up to 4.3 years after vision loss was compared to the visual acuity of 208 NH subjects matched for age and ND4 genotype. The NH subjects were from a LHON registry (REALITY) and from 10 NH studies. A locally estimated scatterplot smoothing (LOESS), non-parametric, local regression model was used to modelize visual acuity curves over time, and linear mixed model was used for statistical inferences. Main Outcome Measures: The main outcome measure was evolution of visual acuity from 12 months after vision loss, when REVERSE and RESCUE patients had been treated with rAAV2/2-ND4. Results: The LOESS curves showed that the BCVA of the treated patients progressively improved from month 12 to 52 after vision loss. At month 48, there was a statistically and clinically relevant difference in visual acuity of −0.33 logarithm of the minimal angle of resolution (LogMAR) (16.5 ETDRS letters equivalent) in favor of treated eyes vs. NH eyes (p &lt; 0.01). Most treated eyes (88.7%) were on-chart at month 48 as compared to 48.1% of the NH eyes (p &lt; 0.01). The treatment effect at last observation remained statistically and clinically significant when adjusted for age and duration of follow-up (−0.32 LogMAR, p &lt; 0.0001). Conclusions: The m.11778G&gt;A LHON patients treated with rAAV2/2-ND4 exhibited an improvement of visual acuity over more than 4 years after vision loss to a degree not demonstrated in NH studies. Clinical Trial Registration: NCT02652767, NCT02652780, NCT03406104, and NCT03295071

Efficacy of exercise therapy in workers with rotator cuff tendinopathy: A systematic review

Objective: To perform a systematic review of randomized controlled trials (RCTs) on the efficacy of therapeutic exercises for workers suffering from rotator cuff (RC) tendinopathy. Methods: A literature search in four bibliographical databases (Pubmed, CINAHL, EMBASE, and PEDro) was conducted from inception up to February 2015. RCTs were included if participants were workers suffering from RC tendinopathy, the outcome measures included work-related outcomes, and at least one of the interventions under study included exercises. The methodological quality of the studies was evaluated with the Cochrane Risk of Bias Assessment tool. Results: The mean methodological score of the ten included studies was 54.4%±17.2%. Types of workers included were often not defined, and work-related outcome measures were heterogeneous and often not validated. Three RCTs of moderate methodological quality concluded that exercises were superior to a placebo or no intervention in terms of function and return-to-work outcomes. No significant difference was found between surgery and exercises based on the results of two studies of low to moderate methodological quality. One study of low methodological quality, comparing a workplacebased exercise program focusing on the participants\u27 work demands to an exercise program delivered in a clinical setting, concluded that the work-based intervention was superior in terms of function and return-to-work outcomes. Conclusion: There is low to moderate-grade evidence that therapeutic exercises provided in a clinical setting are an effective modality to treat workers suffering from RC tendinopathy and to promote return-to-work. Further high quality studies comparing different rehabilitation programs including exercises in different settings with defined workers populations are needed to draw firm conclusions on the optimal program to treat workers

Phenotypic microarrays suggest Escherichia coli ST131 is not a metabolically distinct lineage of extra-intestinal pathogenic E. coli

Extraintestinal pathogenic E. coli (ExPEC) are the major aetiological agent of urinary tract infections (UTIs) in humans. The emergence of the CTX-M producing clone E. coli ST131 represents a major challenge to public health worldwide. A recent study on the metabolic potential of E. coli isolates demonstrated an association between the E. coli ST131 clone and enhanced utilisation of a panel of metabolic substrates. The studies presented here investigated the metabolic potential of ST131 and other major ExPEC ST isolates using 120 API test reagents and found that ST131 isolates demonstrated a lower metabolic activity for 5 of 120 biochemical tests in comparison to non-ST131 ExPEC isolates. Furthermore, comparative phenotypic microarray analysis showed a lack of specific metabolic profile for ST131 isolates countering the suggestion that these bacteria are metabolically fitter and therefore more successful human pathogens

Using data-driven rules to predict mortality in severe community acquired pneumonia

Prediction of patient-centered outcomes in hospitals is useful for performance benchmarking, resource allocation, and guidance regarding active treatment and withdrawal of care. Yet, their use by clinicians is limited by the complexity of available tools and amount of data required. We propose to use Disjunctive Normal Forms as a novel approach to predict hospital and 90-day mortality from instance-based patient data, comprising demographic, genetic, and physiologic information in a large cohort of patients admitted with severe community acquired pneumonia. We develop two algorithms to efficiently learn Disjunctive Normal Forms, which yield easy-to-interpret rules that explicitly map data to the outcome of interest. Disjunctive Normal Forms achieve higher prediction performance quality compared to a set of state-of-the-art machine learning models, and unveils insights unavailable with standard methods. Disjunctive Normal Forms constitute an intuitive set of prediction rules that could be easily implemented to predict outcomes and guide criteria-based clinical decision making and clinical trial execution, and thus of greater practical usefulness than currently available prediction tools. The Java implementation of the tool JavaDNF will be publicly available. © 2014 Wu et al