Polymerase proofreading-associated polyposis (PPAP) is an autosomal dominant cancer predisposition syndrome caused by the inability of the DNA polymerases POLE and POLD1 to proofread newly synthesized DNA strands. Those with PPAP are at increased risk for colorectal cancer and adenoma. Endometrial, ovarian, duodenal, stomach, melanoma, and brain cancers have also been described among affected individuals, but less is known about these extracolonic manifestations, especially malignant brain tumors.
Existing instruments for measuring mobility are inadequate for accurately assessing older people across the broad spectrum of abilities. Like other indices that monitor critical aspects of health such as blood pressure tests, a mobility test for all older acute medical patients provides essential health data. We have developed and validated an instrument that captures essential information about the mobility status of older acute medical patients. Items suitable for a new mobility instrument were generated from existing scales, patient interviews and focus groups with experts. 51 items were pilot tested on older acute medical inpatients. An interval-level unidimensional mobility measure was constructed using Rasch analysis. The final item set required minimal equipment and was quick and simple to administer. The de Morton Mobility Index (DEMMI) was validated on an independent sample of older acute medical inpatients and its clinimetric properties confirmed. The DEMMI is a 15 item unidimensional measure of mobility. Reliability (MDC90), validity and the minimally clinically important difference (MCID) of the DEMMI were consistent across independent samples. The MDC90 and MCID were 9 and 10 points respectively (on the 100 point Rasch converted interval DEMMI scale). The DEMMI provides clinicians and researchers with a valid interval-level method for accurately measuring and monitoring mobility levels of older acute medical patients. DEMMI validation studies are underway in other clinical settings and in the community. Given the ageing population and the importance of mobility for health and community participation, there has never been a greater need for this instrument.
Background Several tests have recently been developed to measure changes in patient strength and functional outcomes in the intensive care unit (ICU). The original Physical Function ICU Test (PFIT) demonstrates reliability and sensitivity. Objective The aims of this study were to further develop the original PFIT, to derive an interval score (the PFIT-s), and to test the clinimetric properties of the PFIT-s. Design A nested cohort study was conducted. Methods One hundred forty-four and 116 participants performed the PFIT at ICU admission and discharge, respectively. Original test components were modified using principal component analysis. Rasch analysis examined the unidimensionality of the PFIT, and an interval score was derived. Correlations tested validity, and multiple regression analyses investigated predictive ability. Responsiveness was assessed using the effect size index (ESI), and the minimal clinically important difference (MCID) was calculated. Results The shoulder lift component was removed. Unidimensionality of combined admission and discharge PFIT-s scores was confirmed. The PFIT-s displayed moderate convergent validity with the Timed “Up & Go” Test (r=−.60), the Six-Minute Walk Test (r=.41), and the Medical Research Council (MRC) sum score (rho=.49). The ESI of the PFIT-s was 0.82, and the MCID was 1.5 points (interval scale range=0–10). A higher admission PFIT-s score was predictive of: an MRC score of ≥48, increased likelihood of discharge home, reduced likelihood of discharge to inpatient rehabilitation, and reduced acute care hospital length of stay. Limitations Scoring of sit-to-stand assistance required is subjective, and cadence cutpoints used may not be generalizable. Conclusions The PFIT-s is a safe and inexpensive test of physical function with high clinical utility. It is valid, responsive to change, and predictive of key outcomes. It is recommended that the PFIT-s be adopted to test physical function in the ICU.
To determine if a programme of progressive resistance exercise, mobilisation and orientation, in addition to usual care, was superior to usual care alone in the prevention of incident delirium in older hospitalised patients.A randomised controlled trial.The study was performed at a secondary referral hospital in Melbourne, Australia between May 2005 and December 2007.648 consecutive medical inpatients aged 65 years or older who had been in hospital for less than 48 h and who did not have delirium.Participants were randomly allocated to a twice-daily programme of progressive resistance exercise tailored to individual ability, mobilisation and orientation in addition to usual care or to usual care alone.Delirium was measured using the Confusion Assessment Method at baseline and every 48 h until discharge. Secondary outcome measures were severity and duration of delirium, discharge destination and length of stay.Delirium occurred in 4.9% (95% CI 2.3% to 7.3%) of the intervention group (15/305) and in 5.9% (20/339; 95% CI 3.8% to 9.2%) of the group receiving usual care. No difference was observed between groups (χ(2); p=0.5). The intervention had no effect on delirium duration, severity, discharge destination or length of stay.A programme of progressive resistance exercise and orientation was not effective in reducing incident delirium in hospitalised elderly patients.
Aim The aim of this study was to describe systematically the best available intervention evidence for children with cerebral palsy ( CP ). Method This study was a systematic review of systematic reviews. The following databases were searched: CINAHL , C ochrane L ibrary, DARE , EMBASE , G oogle S cholar MEDLINE , OTS eeker, PED ro, Psyc BITE , P syc INFO , and speech BITE . Two independent reviewers determined whether studies met the inclusion criteria. These were that (1) the study was a systematic review or the next best available; (2) it was a medical/allied health intervention; and (3) that more than 25% of participants were children with CP . Interventions were coded using the O xford L evels of E vidence; GRADE ; E vidence A lert T raffic L ight; and the I nternational C lassification of F unction, D isability and H ealth. Results Overall, 166 articles met the inclusion criteria (74% systematic reviews) across 64 discrete interventions seeking 131 outcomes. Of the outcomes assessed, 16% (21 out of 131) were graded ‘do it’ (green go); 58% (76 out of 131) ‘probably do it’ (yellow measure); 20% (26 out of 131) ‘probably do not do it’ (yellow measure); and 6% (8 out of 131) ‘do not do it’ (red stop). Green interventions included anticonvulsants, bimanual training, botulinum toxin, bisphosphonates, casting, constraint‐induced movement therapy, context‐focused therapy, diazepam, fitness training, goal‐directed training, hip surveillance, home programmes, occupational therapy after botulinum toxin, pressure care, and selective dorsal rhizotomy. Most (70%) evidence for intervention was lower level (yellow) while 6% was ineffective (red). Interpretation Evidence supports 15 green light interventions. All yellow light interventions should be accompanied by a sensitive outcome measure to monitor progress and red light interventions should be discontinued since alternatives exist.
SIR–In responding to the letters that have been sent regarding our paper1, it is clear we are all passionate about our own specialities; at the same time we believe that the optimal well-being of children with cerebral palsy (CP) must remain at the centre of this debate. We take this opportunity to state that we strongly uphold the principles of evidence-based medicine (EBM), wherein the integration of clinical expertise, client values, and best evidence2 is considered paramount to quality clinical decision-making. The purpose of a systematic review is to summarize the best available evidence. We provided such a summary, but this should not be misread as a clinical ‘cookbook’. We concur with EBM experts that, ‘Systematic reviews can define the boundaries of what is known and what is not known… Systematic reviews can aid, but can never replace, sound clinical reasoning.’3 Our systematic review used strict, clear inclusion and exclusion criteria, with an emphasis on including systematic review levels of evidence. It is important to note that the GRADE criteria that we employed downgrade the quality score in response to methodological limitations.4 In this field, for reasons the corresponding authors have identified, this often resulted in a GRADE evidence quality rating of low or very low, which formed a part of the GRADE recommendation and the assigned traffic light colour. It is plausible that another systematic review with broader (or more specific) inclusion criteria, including other levels of evidence, might produce another result more favourable for interventions predominated by lower levels of evidence. We believe that this is an area for further discussion and exploration by our whole field, regarding how to resolve these dilemmas commonly faced in research. We acknowledge that a three-colour code evidence system may risk oversimplifying complex research data and recommendations for some readers. We also acknowledge some may not favour the ‘review of reviews’ methodology; however, great variation in care occurs and diverse DMCN readership needs exist. In addition to the letters that we are responding to, we have also received positive written and verbal feedback from reputable research, clinical, and parent groups about perceived usefulness of the review, a sign of positive impact for some readers. None of these groups (or we) regard this paper as a stand-alone piece, but rather a platform from where to look further for specific information. A number of concerns from corresponding groups were related to ‘yellow’ interventions. We would like to reiterate what a yellow coding means in this review. Yellow is a prompt to measure individual treatment outcomes as published data does not yet provide absolute certainty about what to expect. Yellow does not mean ‘caution’ as Theologis writes, nor does it mean ‘stop’ as some correspondents imply. Red is the only indication where data prove ineffectiveness or harm and for which we recommend stopping use. We are not arguing that yellow interventions should not be used, because in many situations these interventions constitute best available evidence. It is also conceivable that a number of yellow interventions are more effective than the better-researched green interventions. We are not arguing that green interventions are superior to yellow interventions. It was beyond the scope of this article to compare one treatment to another; rather, we only argued the superiority of an intervention approach when the authors of the systematic reviews reported one convincingly. Systematic yellow measurement data, published in the literature, would provide more clarity for all of us. Professor Graham's group have been world leaders in role modelling this evidence-based cycle of ‘intervene-measure-report’ and we have been long-standing enthusiasts of their seminal work. We agree with Love and Blair that all interventions should be measured, so much so that at our institution systematic outcome measurement is mandated by policy for all services. However, we are also aware of the evidence that indicates professionals in our field do not yet routinely carry out systematic outcome measurement.5 We attempted to highlight situations in which measurement data would be most helpful, since randomized controlled trials (RCTs) are not always possible. As for the concerns raised by Firth, Love and Blair, and Thomason and Graham that parents might misread our article and misguidedly abandon yellow interventions, this independent parent blog appears to provide some evidence to the contrary: http://cpdailyliving.com/cp-alliance-publishes-research-analysis-of-cerebral-palsy-interventions/. We emphasized that discussion with families around choice of intervention is important and is already an essential component of care for clinicians (p. 903). Readers have always been tasked with the important responsibility of translating and incorporating evidence, client values, and clinical expertise to develop appropriate individual care plans. This review does not change this integral component of care. This paper could never make individual recommendations for clinical care; rather it provides a summary of average responses to intervention as reported in (predominantly) systematic review literature. The very notion that researchers measure ‘average’ responses in the heterogeneous condition of CP indeed has limitations. Yet, RCTs are still perceived to be the criterion standard for measuring the effectiveness of an intervention and our hierarchal use of evidence follows published conventions. We agree with Thomason and Graham, and Theologis that in a heterogeneous condition like CP, where assembling large equivalent trial samples is both pragmatically and commercially challenging, other methodologies are critically important. This is why the discussion section included specific recommendations about the importance of using registers, individual patient meta-analyses, and single-system designs (p. 906) in presenting evidence of intervention effectiveness. As active collaborators with the Australian Cerebral Palsy Register we are steadfast in our utilization and reporting of other quality research designs. Rehabilitation interventions are often complex, difficult to define, and may include a number of components.6 Early intervention, single-event multilevel surgery (SEMLS), and neurodevelopmental therapy (NDT) are all examples. When discussing early intervention we used the same terms that authors used in the extracted papers. However, the early intervention field has undergone substantial change since these papers were written, and the field now thinks about intervening in motor function, cognition, and environmental aspects differently. It is also the case that SEMLS interventions include at least 12 months of ‘rehabilitation’ after surgery and components of this overall treatment include orthotics, strength training, and gait training. We also note Mayston and Rosenbloom's perspective that describes NDT as a system of therapy now including many eclectic approaches that have evolved over time. All of these rehabilitation treatments or approaches must stand up to measurement and have in fact been tested in RCTs, the results of which are summarized in the paper. We agree with Scherzer that precision of terminology is now required and is the best way forward for the field. Understanding the ‘active ingredients’ of such complex rehabilitation approaches can only help the upcoming generations of clinicians to be evidence-based practitioners. In this internet-based era where families are active research readers, we believe it would be helpful to families if contemporary NDT therapists used the same terms as others, rather than eclectically adding other approaches into a heterogeneous NDT umbrella. We also hope that they empirically test these approaches, and when reporting findings name the interventions that comprise the experimental group. We agree with Thomason and Graham that orthopaedic management of the hips and spine is best practice and in line with best available evidence. Our review used the definition of active hip surveillance prevention programme (Table I) as coined by Hägglund et al.7 In this definition hip surveillance is a treatment amalgam of many multidisciplinary interventions including surgery.8 So other than the definition of hip surveillance, we are in complete agreement that orthopaedics makes a major contribution to comprehensive hip management, being categorized in our work as green light. McGinley et al.'s8 SEMLS review stated: ‘This systematic review found low levels of evidence to support the use of SEMLS for individuals with CP… Levels of evidence for treatment recommendations would also be correspondingly low’. This is exactly what we reported. Our review criteria allowed us to include more recent RCT data that would substantially update conclusions about a body of evidence. Thomason et al.'s9 SEMLS pilot RCT of n = 19 was not overlooked, but was graded as a ‘weak +’ GRADE recommendation (yellow traffic light) thus not meeting inclusion for changing the total SEMLS evidence grading. If, however, based upon Thomason et al.'s10 more recent longitudinal five-year cohort follow-up of the n = 19 RCT participants, orthopaedic experts believe this is enough evidence to upgrade the recommendation for use of SEMLS evidence then we strongly encourage them to publish an update of their systematic review. Systematic reviews are limited by their time-bound retrospective nature, and publication lag is a genuine source of bias as Rutz et al. appropriately identified. Indeed, we expect – indeed hope! – that GRADE recommendations and traffic light coding of the interventions included in this review will change over time as valid new evidence becomes available. We therefore thank our orthopaedic colleagues for providing expert advice above and beyond what was published in the extracted systematic reviews. Readers of our review should note that although consensus does not yet exist in literature the corresponding orthopaedic experts recommend the following: (1) orthopaedic surgery could be upgraded to a green light based on new longitudinal data from their observational and gait studies; and (2) new muscle data is suggesting that even though botulinum toxin is highly effective, it may have long-term negative effects on muscles and therefore clinicians ought to be watchful. We agree with Love and Blair, Mayston and Rosenbloom, Thomason and Graham, Rutz et al., and Theologis that it would have been preferable to stratify the results by Gross Motor Function Classification System (GMFCS)11 and motor sub-type. This was stated as sought after (p. 898), but not possible due to substantial heterogeneity in the data available in the included papers, and was reported as a limitation. We expect stratification will be possible in the future, since the GMFCS, which was developed and published in the late 90s, has now been adopted as the criterion standard classification for gross motor function. We also agree with Love and Blair that an in-depth systematic discussion of adverse events, rather than the brief discussion for some interventions in Table I of the original document, (pp. 888–897) would have added value to the paper. This was, however, outside the scope of this very large paper but we acknowledge is a study limitation. We agree that it was a study limitation that our multidisciplinary author group did not include medical and allied health practitioners with specific expertise in each area of intervention. The panel, however, was not (as suggested) positively biased towards their own professions, as evident in the ratings of yellow for interventions within the disciplines of speech pathology, psychology, and social work and ‘red’ for two therapy approaches. While such ratings may elicit disagreement from colleagues, the opportunity moving forward is to continually improve the methodological quality of research output at all levels of research design, thus engendering an increased degree of certainty about reported results and subsequent recommendations. Our author group had no personal or commercially-biased perspective on what constitutes good treatment, but rather a consistent perspective on what constitutes good evidence, using widely respected evidence quality filters. In response to Thomason and Graham's remarks about our potential conflict of interest, we confirm again that we did not have any conflict of interest in extracting data from secondary sources for this systematic review. In relation to the five primary sources referred to,12-16 these publications included disclosure statements printed in the public domain, and we quote: ‘The Cerebral Palsy Institute also gratefully acknowledges the unrestricted educational grant received from Allergan to support the project [International Consensus Statements for Botulinum Toxin]. It should be noted that no authors were provided with any funds to participate in the project … Allergan had no access to the manuscripts at any point throughout the project duration and had no right of scientific veto … Potential authors were excluded if they were or had ever been employees of any of the BoNT pharmaceutical companies.’ We have been heartened by the interest in this paper and welcome continued academic discussion. We strongly agree with Autti-Ramo, Eliasson, and Forssberg that the essential next step for the field is to prioritize the development of in-depth, subgroup-specific, valid and patient-oriented, internationally endorsed clinical guidelines, using rigorous, accepted methologies, and involving appropriate consultation. And we strongly agree with Fehlings that using a Delphi methodology to achieve consensus on what expert opinions to include within such recommendations would add rigor and value. Future directions include the use of new forms of analysis such as multiple treatment meta-analyses to produce comparative effect sizes and a ranking of alternate treatment options in relation to a particular outcome of interest. We welcome conductive education and NDT groups (such as Capelovitch, Mayston and Rosenbloom, and Schenker and Sutton) conducting more efficacy research, using rigorous methods, and measuring important and relevant end-points such as participation as Mayston and Rosenbloom propose. We are committed to remaining up to date with any changes to the criterion standard approach to hierarchies of evidence for specific interventions. The lessons learned from this process will, we hope, help us all with our ongoing efforts to ensure that research is translated into practice, so that children with CP receive the most effective treatments based on sound and valid evidence. From the responses to this paper, both formally and informally, we are encouraged that the wider research community will continue to join us in these efforts.
'/%3e%3c/defs%3e%3cpath fill='%23012169' d='M0 0h10080v5040H0z'/%3e%3cpath stroke='%23fff' stroke-width='.6' d='m0 0 6 3m0-3L0 3' clip-path='url(%23b)' transform='scale(840)'/%3e%3cpath stroke='%23e4002b' stroke-width='.4' d='m0 0 6 3m0-3L0 3' clip-path='url(%23c)' transform='scale(840)'/%3e%3cpath stroke='%23fff' stroke-width='840' d='M2520 0v2520M0 1260h5040'/%3e%3cpath stroke='%23e4002b' stroke-width='504' d='M2520 0v2520M0 1260h5040'/%3e%3cg fill='%23fff'%3e%3cuse xlink:href='%23d' x='2520' y='3780'/%3e%3cuse xlink:href='%23a' x='7560' y='4200'/%3e%3cuse xlink:href='%23a' x='6300' y='2205'/%3e%3cuse xlink:href='%23a' x='7560' y='840'/%3e%3cuse xlink:href='%23a' x='8680' y='1869'/%3e%3cuse xlink:href='%23e' x='8064' y='2730'/%3e%3c/g%3e%3c/svg%3e)