Non-viral delivery and optimized optogenetic stimulation of retinal ganglion cells led to behavioral restoration of vision

Stimulation of retinal neurons using optogenetics via use of chanelrhodopsin-2 (ChR2) has opened up a new direction for restoration of vision for treatment of retinitis pigmentosa (RP). Here, we report non-viral in-vivo electroporation of degenerated retina of adult RP-mice with ChR2-plasmids and subsequent in-vivo imaging of retina to confirm expression. Further, we demonstrate that in addition to efficient non-viral delivery of ChR2 to a specific retinal layer, threshold level of stimulation light needs to be delivered onto the retina for achieving successful behavioral outcome. Measurement of intensity of light reaching the retina of RP-mouse models along with geometrical optics simulation of light propagation in the eye is reported in order to determine the stimulating source position for optimal light delivery to the retina. The light-guided navigation of mice with ChR2 expressing retinal ganglion cells was found to be significantly improved over a long distance in correlation with stimulation intensity

Paramedics’ Confidence and Perceived Competence When Attending to Varied Patient Presentations: A Mixed-Method Study

Purpose: Paramedics are routinely called to patients presenting with mental health concerns. Previous literature suggests paramedics find this patient group challenging. However, no study has investigated whether paramedics find mental health presentations (MHP) more challenging relative to other patient presentations, or whether certain paramedic variables relate to their perceived ability to manage MHP. This study investigates differences in paramedics’ perceived ability to attend to MHP compared to other patient presentations, and whether their perceived ability is related to their level of experience or location of work (metropolitan or rural). The study also explores paramedic’s experiences and perspectives of MHP. Method: Operational paramedics in Australia (n = 138) completed a survey assessing their perceived ability to respond to mental health, cardiac, respiratory, and trauma-related presentations. A repeated measures ANOVA tested differences in perceived ability between these patient presentations. T-tests and Pearson’s correlations were conducted to determine whether years of experience or location of work related to their perceived ability for MHP. Nine paramedics were also interviewed, and a thematic analysis conducted to gain insight into paramedic’s experiences and perspectives of MHP. Results: Paramedics reported a significantly lower perceived ability to respond to MHP relative to each other patient presentation measured. No relationships were found between a paramedic’s perceived ability to respond to MHP and their length of work experience or location of work. Interviews with paramedics revealed four superordinate themes: 1) inconsistent conceptualization of their role, 2) feelings of helplessness and frustration, 3) stigmatized views of patients with a mental illness, and 4) inconsistent views of knowledge and learning relating to MHP. Conclusions: Paramedics believe they have a significantly poorer ability to respond to MHP relative to other patient presentations. Education and training focused on defining a paramedic’s role for MHP as well as reducing stigmatized views of patients with a mental illness may improve paramedic’s care of this cohort of patients

Measurement and characterisation of individual differences in need for cognition.

This thesis investigated the measurement of differences between people in tendency to engage in effortful thought. Findings from this research will improve measurement in future research, while also providing insights into the motivation behind this tendency, with implications for diverse applications such as education, career selection, and prejudice

Family firm configurations for high performance: The role of entrepreneurship and ambidexterity

The performance drivers of family firms have spawned considerable research interest. Almost exclusively this research has relied on independent sets of explanatory variables in linear analyses. These analyses mask the complex interdependencies that are likely to exist among key success factors, leading to faulty theory and misspecified implications for practice. As treatment, we propose a configuration approach to family firm performance that accounts for complex interdependencies among entrepreneurial, innovation and family influence conditions. Using a fuzzy set qualitative comparative analysis (fsQCA) of a sample of 129 Finnish family firms, we identify sufficient conditions with regards to the existence or absence of antecedent conditions to family firm performance. These conditions include entrepreneurial orientation, exploration and exploitation activities that form causal paths towards family firm performance. To enrich our analysis, we theorize and empirically analyse how these conditions might differ in family firms with high and low levels of family influence. We deepen the current understanding of configurations that promote the performance of family firms, offer important implications for theory and practice, and set new directions for future research on the strategic management of family firms. Our results are also virtually identical and insensitive to change across subjective and objective performance measures

Dialysis Initiation in Patients With Chronic Coronary Disease and Advanced Chronic Kidney Disease in ISCHEMIA-CKD

BACKGROUND: In participants with concomitant chronic coronary disease and advanced chronic kidney disease (CKD), the effect of treatment strategies on the timing of dialysis initiation is not well characterized. METHODS AND RESULTS: In ISCHEMIA‐CKD (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches–Chronic Kidney Disease), 777 participants with advanced CKD and moderate or severe ischemia were randomized to either an initial invasive or conservative management strategy. Herein, we compare the proportion of randomized participants with non–dialysis‐requiring CKD at baseline (n=362) who initiated dialysis and compare the time to dialysis initiation between invasive versus conservative management arms. Using multivariable Cox regression analysis, we also sought to identify the effect of invasive versus conservative chronic coronary disease management strategies on dialysis initiation. At a median follow‐up of 23 months (25th–75th interquartile range, 14–32 months), dialysis was initiated in 18.9% of participants (36/190) in the invasive strategy and 16.9% of participants (29/172) in the conservative strategy (P=0.22). The median time to dialysis initiation was 6.0 months (interquartile range, 3.0–16.0 months) in the invasive group and 18.2 months (interquartile range, 12.2–25.0 months) in the conservative group (P=0.004), with no difference in procedural acute kidney injury rates between the groups (7.8% versus 5.4%; P=0.26). Baseline clinical factors associated with earlier dialysis initiation were lower baseline estimated glomerular filtration rate (hazard ratio [HR] associated with 5‐unit decrease, 2.08 [95% CI, 1.72–2.56]; P<0.001), diabetes (HR, 2.30 [95% CI, 1.28–4.13]; P=0.005), hypertension (HR, 7.97 [95% CI, 1.09–58.21]; P=0.041), and Hispanic ethnicity (HR, 2.34 [95% CI, 1.22–4.47]; P=0.010). CONCLUSIONS: In participants with non–dialysis‐requiring CKD in ISCHEMIA‐CKD, randomization to an invasive chronic coronary disease management strategy (relative to a conservative chronic coronary disease management strategy) is associated with an accelerated time to initiation of maintenance dialysis for kidney failure

Apraxia and motor dysfunction in corticobasal syndrome

Background: Corticobasal syndrome (CBS) is characterized by multifaceted motor system dysfunction and cognitive disturbance; distinctive clinical features include limb apraxia and visuospatial dysfunction. Transcranial magnetic stimulation (TMS) has been used to study motor system dysfunction in CBS, but the relationship of TMS parameters to clinical features has not been studied. The present study explored several hypotheses; firstly, that limb apraxia may be partly due to visuospatial impairment in CBS. Secondly, that motor system dysfunction can be demonstrated in CBS, using threshold-tracking TMS, and is linked to limb apraxia. Finally, that atrophy of the primary motor cortex, studied using voxel-based morphometry analysis (VBM), is associated with motor system dysfunction and limb apraxia in CBS.   Methods: Imitation of meaningful and meaningless hand gestures was graded to assess limb apraxia, while cognitive performance was assessed using the Addenbrooke's Cognitive Examination - Revised (ACE-R), with particular emphasis placed on the visuospatial subtask. Patients underwent TMS, to assess cortical function, and VBM.   Results: In total, 17 patients with CBS (7 male, 10 female; mean age 64.4+/2 6.6 years) were studied and compared to 17 matched control subjects. Of the CBS patients, 23.5% had a relatively inexcitable motor cortex, with evidence of cortical dysfunction in the remaining 76.5% patients. Reduced resting motor threshold, and visuospatial performance, correlated with limb apraxia. Patients with a resting motor threshold <50% performed significantly worse on the visuospatial sub-task of the ACE-R than other CBS patients. Cortical function correlated with atrophy of the primary and pre-motor cortices, and the thalamus, while apraxia correlated with atrophy of the pre-motor and parietal cortices.   Conclusions: Cortical dysfunction appears to underlie the core clinical features of CBS, and is associated with atrophy of the primary motor and pre-motor cortices, as well as the thalamus, while apraxia correlates with pre-motor and parietal atrophy

The impact of structured self-monitoring of blood glucose on clinical, behavioral, and psychosocial outcomes among adults with non-insulin-treated type 2 diabetes: a systematic review and meta-analysis

BackgroundSelf-monitoring of blood glucose (SMBG) is considered of little clinical benefit for adults with non-insulin-treated type 2 diabetes, but no comprehensive review of a structured approach to SMBG has been published to date.PurposeTo conduct a systematic review and meta-analysis of the impact of sSMBG on HbA1c, treatment modifications, behavioral and psychosocial outcomes, and; examine the moderating effects of sSMBG protocol characteristics on HbA1c.Data sourcesFour databases searched (November 2020; updated: February 2022).Study selectionInclusion criteria: non-randomized and randomized controlled trials (RCTs) and prospective observational studies; reporting effect of sSMBG on stated outcomes; among adults (≥18 years) with non-insulin-treated type 2 diabetes. Studies excluded if involving children or people with insulin-treated or other forms of diabetes.Data extraction and analysisOutcome data extracted, and risk of bias/quality assessed independently by two researchers. Meta-analysis was conducted for RCTs, and moderators explored (HbA1c only).Data synthesisFrom 2,078 abstracts, k=23 studies were included (N=5,372). Risk of bias was evident and study quality was low. Outcomes assessed included: HbA1c (k=23), treatment modification (k=16), psychosocial/behavioral outcomes (k=12). Meta-analysis revealed a significant mean difference favoring sSMBG in HbA1c (-0·29%, 95% CI: -0·46 to -0·11, k=13) and diabetes self-efficacy (0.17%, 95% CI: 0.01 to 0.33, k=2). Meta-analysis revealed no significant moderating effects by protocol characteristics.LimitationsFindings limited by heterogeneity in study designs, intervention characteristics, and psychosocial assessments.ConclusionA small positive effect of sSMBG on HbA1c and diabetes self-efficacy was observed. Narrative synthesis of sSMBG intervention characteristics may guide future implementation.PROSPERO registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020208857, identifier CRD42020208857

Analysis of COVID-19 Guideline Quality and Change of Recommendations: A Systematic Review.

Background Hundreds of coronavirus disease 2019 (COVID-19) clinical practice guidelines (CPGs) and expert consensus statements have been developed and published since the outbreak of the epidemic. However, these CPGs are of widely variable quality. So, this review is aimed at systematically evaluating the methodological and reporting qualities of COVID-19 CPGs, exploring factors that may influence their quality, and analyzing the change of recommendations in CPGs with evidence published. Methods We searched five electronic databases and five websites from 1 January to 31 December 2020 to retrieve all COVID-19 CPGs. The assessment of the methodological and reporting qualities of CPGs was performed using the AGREE II instrument and RIGHT checklist. Recommendations and evidence used to make recommendations in the CPGs regarding some treatments for COVID-19 (remdesivir, glucocorticoids, hydroxychloroquine/chloroquine, interferon, and lopinavir-ritonavir) were also systematically assessed. And the statistical inference was performed to identify factors associated with the quality of CPGs. Results We included a total of 92 COVID-19 CPGs developed by 19 countries. Overall, the RIGHT checklist reporting rate of COVID-19 CPGs was 33.0%, and the AGREE II domain score was 30.4%. The overall methodological and reporting qualities of COVID-19 CPGs gradually improved during the year 2020. Factors associated with high methodological and reporting qualities included the evidence-based development process, management of conflicts of interest, and use of established rating systems to assess the quality of evidence and strength of recommendations. The recommendations of only seven (7.6%) CPGs were informed by a systematic review of evidence, and these seven CPGs have relatively high methodological and reporting qualities, in which six of them fully meet the Institute of Medicine (IOM) criteria of guidelines. Besides, a rapid advice CPG developed by the World Health Organization (WHO) of the seven CPGs got the highest overall scores in methodological (72.8%) and reporting qualities (83.8%). Many CPGs covered the same clinical questions (it refers to the clinical questions on the effectiveness of treatments of remdesivir, glucocorticoids, hydroxychloroquine/chloroquine, interferon, and lopinavir-ritonavir in COVID-19 patients) and were published by different countries or organizations. Although randomized controlled trials and systematic reviews on the effectiveness of treatments of remdesivir, glucocorticoids, hydroxychloroquine/chloroquine, interferon, and lopinavir-ritonavir for patients with COVID-19 have been published, the recommendations on those treatments still varied greatly across COVID-19 CPGs published in different countries or regions, which may suggest that the CPGs do not make sufficient use of the latest evidence. Conclusions Both the methodological and reporting qualities of COVID-19 CPGs increased over time, but there is still room for further improvement. The lack of effective use of available evidence and management of conflicts of interest were the main reasons for the low quality of the CPGs. The use of formal rating systems for the quality of evidence and strength of recommendations may help to improve the quality of CPGs in the context of the COVID-19 pandemic. During the pandemic, we suggest developing a living guideline of which recommendations are supported by a systematic review for it can facilitate the timely translation of the latest research findings to clinical practice. We also suggest that CPG developers should register the guidelines in a registration platform at the beginning for it can reduce duplication development of guidelines on the same clinical question, increase the transparency of the development process, and promote cooperation among guideline developers all over the world. Since the International Practice Guideline Registry Platform has been created, developers could register guidelines prospectively and internationally on this platform

Study Protocol for the COVID-19 Pandemic Adjustment Survey (CPAS): A Longitudinal Study of Australian Parents of a Child 0–18 Years

Background: The COVID-19 pandemic presents significant risks to the mental health and wellbeing of Australian families. Employment and economic uncertainty, chronic stress, anxiety, and social isolation are likely to have negative impacts on parent mental health, couple and family relationships, as well as child health and development. Objective: This study aims to: (1) provide timely information on the mental health impacts of the emerging COVID-19 crisis in a close to representative sample of Australian parents and children (0–18 years), (2) identify adults and families most at risk of poor mental health outcomes, and (3) identify factors to target through clinical and public health intervention to reduce risk. Specifically, this study will investigate the extent to which the COVID-19 pandemic is associated with increased risk for parents’ mental health, lower well-being, loneliness, and alcohol use; parent-parent and parent-child relationships (both verbal and physical); and child and adolescent mental health problems. Methods: The study aims to recruit a close to representative sample of at least 2,000 adults aged 18 years and over living in Australia who are parents of a child 0–4 years (early childhood, N = 400), 5–12 years (primary school N = 800), and 13–18 years (secondary school, N = 800). The design will be a longitudinal cohort study using an online recruitment methodology. Participants will be invited to complete an online baseline self-report survey (20 min) followed by a series of shorter online surveys (10 min) scheduled every 2 weeks for the duration of the COVID-19 pandemic (i.e., estimated to be 14 surveys over 6 months). Results: The study will employ post stratification weights to address differences between the final sample and the national population in geographic communities across Australia. Associations will be analyzed using multilevel modeling with time-variant and time-invariant predictors of change in trajectory over the testing period. Conclusions: This study will provide timely information on the mental health impacts of the COVID-19 crisis on parents and children in Australia; identify communities, parents, families, and children most at risk of poor outcomes; and identify potential factors to address in clinical and public health interventions to reduce risk