Supported Playgroups and Parent Groups Initiative (SPPI) outcomes evaluation

The Victorian Department of Education and Early Childhood Development‟s (DEECD) mission is to ensure a high-quality and coherent birth to adulthood learning and development system to build the capacity of every young Victorian. DEECD‟s Programs and Partnerships Division within its Early Childhood and Development Group has responsibility for programs supporting the health, development and learning of Victoria‟s young children, including kindergarten, maternal and child health, early childhood intervention services, inclusion supports, support for Best Start partnerships, Aboriginal early childhood programs, capital funding for children‟s centres, and the Victorian Supported Playgroups and Parent Groups Initiative. It undertakes this role in partnership with the nine DEECD regions across Victoria, local governments, service provider organisations and other key stakeholders. The division commissioned Urbis to undertake an evaluation of the impact and outcomes of the Supported Playgroups and Parent Groups Initiative (SPPI). Through the evaluation, DEECD sought to determine the impact of supported playgroups on: - parents' social networking and supports - parenting skills and confidence - knowledge and use of early childhood services - parent–child relationships - activities in the home. It was also hoped that the evaluation findings were to contribute to the evidence base for supported playgroups

Improving efficiency in stroke trials: an exploration of methods to improve the use of the modified Rankin Scale in acute stroke trials

The modified Rankin Scale (mRS) is the preferred outcome measure in stroke trials. Typically, mRS assessment is based on a clinician’s rating of a patient interview and interobserver variability is common. Meta-analysis suggests an overall reliability of k=0.46 but this may be less (k=0.25) in multi-centre studies. Mandatory training in mRS assessment is employed in most trials to mitigate this but the problem persists. Variability in assigning outcomes may lead to endpoint misclassification increasing the challenge of accurately demonstrating a treatment effect. We aimed to assess the impact of endpoint misclassification on trial power and explore methods to improve the use of the mRS in acute stroke trials. First we used the mRS outcome distributions of previous phase III randomised controlled trials (RCT) in stroke (NXY059 study and tPA NINDS study) to perform statistical simulations. We generated power estimates and sample sizes from simulated mRS studies under various combinations of sample size, mRS reliability and adjudication panel size. Simulations suggest that the potential benefit of improving mRS reliability from k 0.25 to k 0.5, k 0.7 or k 0.9 may allow a reduction in sample size of n= 386, n= 490 or n= 488 in a typical n=2000 RCT. We then developed a method for providing group adjudication of mRS endpoints and examined the feasibility, reliability and validity of its use in a multicentre clinical trial. We conducted a “virtual” acute stroke trial across 14 UK sites. Local mRS interviews were scored as normal but also recorded to digital video camera. Video clips were uploaded via secure web portal for scoring by adjudication committee reviewers. We demonstrated excellent technical success rates with acceptability to both participants and investigators. 370 participants were included in our “virtual” acute stroke trial and 563 mRS video assessments were uploaded for central review. 96% (538/563) of study visits resulted in an adjudicated mRS score. At 30 and 90 days respectively, 57.5% (161/280) and 50.8% (131/258) of clips were misclassified. Agreement was measured using kappa statistics (k/kw) and intraclass correlation coefficient. Agreement between the adjudication committee was very good (30 days kw 0.85 [95%CI 0.81-0.86], 90 days kw 0.86 [95% CI 0.82-0.88]) with no significant or systematic bias in mRS scoring in comparison to the local mRS. We demonstrated criterion and construct validity of centrally adjudicated mRS scores through comparison with the locally assigned mRS score and other measures known to affect stroke outcome including baseline NIHSS (bNIHSS), Systolic Blood Pressure (SBP), blood glucose and home time. We studied our cohort of mRS video clips to identify any features predictive of variability in mRS scoring. Patient specific variables included participant age, pre stroke mRS, baseline stroke severity as graded by baseline NIHSS (bNIHSS) and presence of language disorder. Interview specific variables included length of interview, poor sound quality, location of the interview, use of a proxy or discussion of prior disability. At both 30 and 90 days only “interview length” was a significant predictor of agreement in mRS scoring. Using a sample of mRS video clips in English and Mandarin, we conducted a pilot study to assess the effect of translation of mRS interviews on interobserver reliability. The interobserver reliability of the translated mRS assessments was similar to native language clips (Native (n=69) kw 0.91 [95%CI 0.86-0.99], Translated (n=89) kw 0.90 [95% CI 0.83-0.96]). We then incorporated a translation step into the central adjudication model using our existing web portal. Inter observer reliability seen in the modified clips (kw 0.85 [95% CI 0.74-0.95]) was similar to that seen in the original video files (kw 0.88 [95% CI 0.78-0.99]). Finally we aimed to investigate the ability of raters to detect more subtle degrees of disability within mRS ranks through blinded assessment of pairs of clips with matching mRS grades. These pairs contained either two clips with full agreement in mRS grade at initial group review or one clip with full agreement and one clip where scores were skewed in the direction of “more” or “less” disability. Pairs were randomly assigned to multiple raters. We could not identify any reliable pattern in identification of the “less disabled” mRS clip. More sensitive grading of the mRS with “good” or “bad” forms of each grade is not reliable on the basis of this exploratory study. Perhaps alternative methods of converting the ordinal ranks of the mRS scale into a more continuous distribution should be investigated; such as the use of a mean mRS score following multiple mRS ratings. Prior estimates of mRS reliability in multicentre studies are poor [k=0.25]. The risks of endpoint misclassification affecting trial power are substantial. Simulations suggest that the effect of improving interobserver reliability and multiple mRS assessments may reduce study sample size by 25%, resulting in substantial ethical and financial benefits. Agreement between our adjudication committee was good [k=0.59(95% CI:0.53-0.63), kw=0.86(95% CI:0.82-0.88)]. Central review may bring many additional potential benefits: “expert” review, quality control and improved blinding in complex trial design. Central adjudication of mRS assessments is feasible, reliable and valid, including the use of translated mRS assessments. This model of outcome assessment has been incorporated into four ongoing large clinical trials: CLEAR-3, MISTIE-3, EUROHYP-1 and SITS-OPEN

Integrated family support project outcome evaluation

The Integrated Family Support Project (IFSP) was established in late 2007 as a three year pilot project to develop a model for collaboration between government and nongovernment agencies and families in the Australian Capital Territory (ACT) who needed coordinated support. Framed by a strengths perspective, the program sought to work with families early in the life of the child and life of the problem, before the problems necessitated statutory child protection intervention, or in the early stages of statutory involvement. The IFSP was jointly funded for three years by the Commonwealth Department of Families, Housing, Community Services and Indigenous Affairs (FaHCSIA) and the ACT Department of Disability, Housing and Community Services (DHCS). It built upon a previous 12 month trial project, and ceased in November 2010 at the conclusion of funding. DHCS commissioned the Institute of Child Protection Studies (ICPS) at the Australian Catholic University (ACU) to develop an evaluation framework for the IFSP, provide sixmonthly progress reports after progress workshops, implement a medium-term process evaluation in 2009 and an outcome evaluation in 2010. This document reports the outcome evaluation

Tips for writing a good recommendation letter

Bias exists in letters of recommendation, and it is reflected in the language used to describe and evaluate different candidates for countless opportunities in academia. Professional organizations are becoming more aware of this issue, and are pursuing avenues to address it. This paper discusses the type of information, that is, useful to have on hand when writing a recommendation letter, the structure of the letter, a process to follow for proof reading, when to say no, a compilation of additional resources, and tips for people asking for recommendation letters. Specifically, we discuss common grammar mistakes, the purpose of each portion of the letter, and ways conscious and unconscious bias can influence wording and structure. This paper is intended to provide a single place where people can go to learn all of the basics needed to write a strong recommendation letter, as currently available letter writing resources in the space physics community tend to focus on one aspect of letter writing

Tips for writing a good recommendation letter

Bias exists in letters of recommendation, and it is reflected in the language used to describe and evaluate different candidates for countless opportunities in academia. Professional organizations are becoming more aware of this issue, and are pursuing avenues to address it. This paper discusses the type of information, that is, useful to have on hand when writing a recommendation letter, the structure of the letter, a process to follow for proof reading, when to say no, a compilation of additional resources, and tips for people asking for recommendation letters. Specifically, we discuss common grammar mistakes, the purpose of each portion of the letter, and ways conscious and unconscious bias can influence wording and structure. This paper is intended to provide a single place where people can go to learn all of the basics needed to write a strong recommendation letter, as currently available letter writing resources in the space physics community tend to focus on one aspect of letter writing

Defining a therapeutic window for kinase inhibitors in leukemia to avoid neutropenia

Neutropenia represents one of the major dose-limiting toxicities of many current cancer therapies. To circumvent the off-target effects of cytotoxic chemotherapeutics, kinase inhibitors are increasingly being used as an adjunct therapy to target leukemia. In this study, we conducted a screen of leukemic cell lines in parallel with primary neutrophils to identify kinase inhibitors with the capacity to induce apoptosis of myeloid and lymphoid cell lines whilst sparing primary mouse and human neutrophils. We have utilized a high-throughput live cell imaging platform to demonstrate that cytotoxic drugs have limited effects on neutrophil viability but are toxic to hematopoietic progenitor cells, with the exception of the topoisomerase I inhibitor SN-38. The parallel screening of kinase inhibitors revealed that mouse and human neutrophil viability is dependent on cyclin-dependent kinase (CDK) activity but surprisingly only partially dependent on PI3 kinase and JAK/STAT signaling, revealing dominant pathways contributing to neutrophil viability. Mcl-1 haploinsufficiency sensitized neutrophils to CDK inhibition, demonstrating that Mcl-1 is a direct target for CDK inhibitors. This study reveals a therapeutic window for the kinase inhibitors BEZ235, BMS-3, AZD7762, and (R)-BI-2536 to induce apoptosis of leukemia cell lines whilst maintaining immunocompetence and hemostasis

Accurate prediction of clinical stroke scales and improved biomarkers of motor impairment from robotic measurements

Objective: One of the greatest challenges in clinical trial design is dealing with the subjectivity and variability introduced by human raters when measuring clinical end-points. We hypothesized that robotic measures that capture the kinematics of human movements collected longitudinally in patients after stroke would bear a significant relationship to the ordinal clinical scales and potentially lead to the development of more sensitive motor biomarkers that could improve the efficiency and cost of clinical trials. Materials and methods: We used clinical scales and a robotic assay to measure arm movement in 208 patients 7, 14, 21, 30 and 90 days after acute ischemic stroke at two separate clinical sites. The robots are low impedance and low friction interactive devices that precisely measure speed, position and force, so that even a hemiparetic patient can generate a complete measurement profile. These profiles were used to develop predictive models of the clinical assessments employing a combination of artificial ant colonies and neural network ensembles. Results: The resulting models replicated commonly used clinical scales to a cross-validated R2 of 0.73, 0.75, 0.63 and 0.60 for the Fugl-Meyer, Motor Power, NIH stroke and modified Rankin scales, respectively. Moreover, when suitably scaled and combined, the robotic measures demonstrated a significant increase in effect size from day 7 to 90 over historical data (1.47 versus 0.67). Discussion and conclusion: These results suggest that it is possible to derive surrogate biomarkers that can significantly reduce the sample size required to power future stroke clinical trials

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

Background: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. Methods: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. Findings: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96–1·28). Interpretation: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. Funding: National Institute for Health Research Health Services and Delivery Research Programme