Pancreatic cancer prognosis is predicted by an ATAC-array technology for assessing chromatin accessibility.

Unlike other malignancies, therapeutic options in pancreatic ductal adenocarcinoma (PDAC) are largely limited to cytotoxic chemotherapy without the benefit of molecular markers predicting response. Here we report tumor-cell-intrinsic chromatin accessibility patterns of treatment-naïve surgically resected PDAC tumors that were subsequently treated with (Gem)/Abraxane adjuvant chemotherapy. By ATAC-seq analyses of EpCAM+ PDAC malignant epithelial cells sorted from 54 freshly resected human tumors, we show here the discovery of a signature of 1092 chromatin loci displaying differential accessibility between patients with disease free survival (DFS) < 1 year and patients with DFS > 1 year. Analyzing transcription factor (TF) binding motifs within these loci, we identify two TFs (ZKSCAN1 and HNF1b) displaying differential nuclear localization between patients with short vs. long DFS. We further develop a chromatin accessibility microarray methodology termed "ATAC-array", an easy-to-use platform obviating the time and cost of next generation sequencing. Applying this methodology to the original ATAC-seq libraries as well as independent libraries generated from patient-derived organoids, we validate ATAC-array technology in both the original ATAC-seq cohort as well as in an independent validation cohort. We conclude that PDAC prognosis can be predicted by ATAC-array, which represents a low-cost, clinically feasible technology for assessing chromatin accessibility profiles.

A modified Delphi consensus study to identify UK osteopathic profession research priorities.

There is an increasing emphasis to take an evidence-based approach to healthcare. To obtain evidence relevant to the osteopathic profession a clear research direction is required based on the views of stakeholders in the osteopathic profession. A modified Delphi consensus approach was conducted to explore the views of osteopaths and patients regarding research priorities for osteopathy. Osteopaths and patients were invited to complete an online questionnaire survey (n = 145). Round 1 requested up to 10 research priority areas and the rationale for their selection. All of the themes from Round 1 were fed back verbatim, and in Round 2 participants were asked to rank the importance of the research priorities on a 5-point Likert scale. Finally, in Round 3 participants were asked to rank the importance of a refined list of research topics which had reached consensus. Descriptive analysis and use of Kendall's coefficient of concordance enabled interpretation of consensus. The response rate for Round 1 was 87.9% and identified 610 research priority areas. Round 2 identified 69 research themes as important, and Round 3 identified 20 research priority topic areas covering four themes: effectiveness of osteopathic treatment (7 areas prioritised), role of osteopathy: the management of four conditions were prioritised, risks with osteopathic treatment (two areas prioritised) and outcomes of osteopathic treatment (two areas prioritised). The findings will be taken forward to develop the research strategy for osteopathy.

Development of a data collection tool to profile osteopathic practice: use of a nominal group technique to enhance clinician involvement.

INTRODUCTION: Little is known about the profile of osteopathic care in the United Kingdom (UK). To address this, a standardised data collection (SDC) tool was developed to record patient-based data within private practice. METHODS: The development of the SDC tool took place within a national network of research groups (hubs) created by the National Council for Osteopathic Research (NCOR); nominal groups were created from the hub network. A Nominal Group Technique (NGT) was used to promote maximum involvement by clinicians and increase ownership of the process: this approach encouraged generation of ideas around specific topics. Following several rounds of iteration, a draft tool was created, followed by a three stage testing process to identify omissions, unnecessary jargon, ambiguities, and any regional differences. RESULTS: The tool developed for a national use by UK osteopaths consisted of 65 items. These were divided into specific sections for patient or clinician completion. The section for patient completion collected data concerning demographic and symptom data. Clinicians provided data concerning treatment provided, advice to promote self-management and avoidance of symptom recurrence, outcome information, service data concerned with waiting times, the number of treatments delivered, and the necessity for referral. CONCLUSION: The tool development process produced a data collection tool aimed to collect snapshot data across the osteopathic profession. The national pilot of the tool will identify changes required, and any barriers to its use by busy professionals.

A profile of osteopathic care in private practices in the United Kingdom: a national pilot using standardised data collection.

Increasing interest is being shown in osteopathy on a national and international basis. Since little prospective data had been available concerning the day-to-day practice of the profession, a standardised data collection tool was developed to try and address this issue. The tool development process has been described in an earlier paper. The standardised data collection (SDC) tool underwent national piloting between April and July 2009 in United Kingdom private practices. Osteopaths volunteered to participate and collected data on consecutive new patients or patients presenting with a new symptom episode for a period of one month; follow-up data were collected for a further two months. A total of 1630 completed datasets from the SDC pilot were analysed by the project team. Data generated from the national pilot showed that lumbar symptoms were the most commonly presented in patients (36%), followed by cervical spine (15%), sacroiliac/pelvic/groin (7.9%), head/facial area (7%), shoulder (6.8%), and thoracic spine (6%). A total of 48.8% of patients reported comorbidities, the most common being hypertension (11.7%), followed by asthma (6.6%), and arthritis (5.7%). Outcome data were collected looking at the patients' response to treatment, and any form of treatment reactions. The profiling information collected using the SDC tool provides a contemporary picture of osteopathic practice in the United Kingdom.

A phase 1 trial of imatinib, bevacizumab, and metronomic cyclophosphamide in advanced colorectal cancer.

BACKGROUND: This phase 1 clinical trial was conducted to determine the safety, maximum-tolerated dose (MTD), and pharmacokinetics of imatinib, bevacizumab, and metronomic cyclophosphamide in patients with advanced colorectal cancer (CRC). METHODS: Patients with refractory stage IV CRC were treated with bevacizumab 5 mg kg(-1) i.v. every 2 weeks (fixed dose) plus oral cyclophosphamide q.d. and imatinib q.d. or b.i.d. in 28-day cycles with 3+3 dose escalation. Response was assessed every two cycles. Pharmacokinetics of imatinib and cyclophosphamide and circulating tumour, endothelial, and immune cell subsets were measured. RESULTS: Thirty-five patients were enrolled. Maximum-tolerated doses were cyclophosphamide 50 mg q.d., imatinib 400 mg q.d., and bevacizumab 5 mg kg(-1) i.v. every 2 weeks. Dose-limiting toxicities (DLTs) included nausea/vomiting, neutropaenia, hyponatraemia, fistula, and haematuria. The DLT window required expansion to 42 days (1.5 cycles) to capture delayed toxicities. Imatinib exposure increased insignificantly after adding cyclophosphamide. Seven patients (20%) experienced stable disease for >6 months. Circulating tumour, endothelial, or immune cells were not associated with progression-free survival. CONCLUSION: The combination of metronomic cyclophosphamide, imatinib, and bevacizumab is safe and tolerable without significant drug interactions. A subset of patients experienced prolonged stable disease independent of dose level.

Classification of movement disorders.

Classification of diseases aids understanding and activity by creating an overview. No single classification can serve all purposes, and it is helpful to be aware of the range of methods available and to understand what they set out to achieve. This article focuses on factors that help the interaction between clinicians and radiologists, with the aim of clarifying how these schemes are generated.

Two-year placebo-controlled trial of botulinum toxin A for leg spasticity in cerebral palsy.

BACKGROUND: The controlled evidence favoring botulinum toxin A (BtA) treatment for spasticity in cerebral palsy is based on short-term studies. METHODS: We conducted a randomized, double-blind, placebo-controlled, parallel-group study of BtA (Dysport) for leg spasticity in 64 children with cerebral palsy. For 2 years, the children received trial injections of up to 30 mu/kg every 3 months if clinically indicated. RESULTS: For the primary endpoints of Gross Motor Function Measure (GMFM) and Pediatric Evaluation of Disability Index (PEDI) scaled scores at 2 years (trough rather than peak effect), there were no differences between the mean change scores of each group. For the GMFM total score, the 95% CI of -4.81 to 1.90 excluded a 5-point difference in either direction, and a 2-point benefit with 95% confidence. There were no differences in adverse events. CONCLUSIONS: There was no evidence of cumulative or persisting benefit from repeated botulinum toxin A (BtA) at the injection cycle troughs at 1 year or 2 years. The dose was not enough to change spasticity measures and thus GMFM in this heterogeneous group. Ceiling effects in GMFM and Pediatric Evaluation of Disability Index (PEDI) may have reduced responsiveness. This finding does not deny the value, individually, of single injection cycles or prove that repeating them is unhelpful. In this regard, BtA treatment can be viewed in the same light as other temporary measures to relieve spasticity, such as oral or intrathecal agents: there is no evidence of continuing benefit if the treatment ceases. The study provides long-term, fully controlled adverse event data and has not revealed any long-term adverse effects.

Management of spasticity in adults: practical application of botulinum toxin.

Spasticity, characterized by increased muscle tone, exaggerated stretch reflexes, and abnormal limb posture, is a common sequel of central nervous system pathology. Historically, medicinal treatments have been of limited efficacy. This review discusses the clinical features of spasticity, the functional and pathological consequences, and treatment. It reviews the most common patterns of spasticity encountered in the upper and lower limbs and focuses on focal treatment of spastic muscles with the three commercially available botulinum toxins Botox, Dysport, and Myobloc/NeuroBloc. It addresses practical details such as muscle selection and identification, drug dilution, and doses.

Chronic pain as perceived by older people: a qualitative study.

BACKGROUND: the practical issues confronting older people who suffer chronic pain may not be tackled in a pain clinic setting and little is known of their strategies for coping. They seem to have little or no information on how to improve the quality of their lives or on resources available to them. AIM: the aim of this study was to ascertain from older people the practical, physical and psychosocial limitations they faced because of chronic pain, and the strategies they used to deal with them. METHOD: a qualitative approach to generating data was chosen using a Grounded Theory approach and unstructured interviews. Sixty-three people ranging from 60 to 87 years of age participated in the study. Audio-tapes were transcribed verbatim. The material was coded and collapsed into themes. RESULTS: two main themes emerged: (i) the desire for independence and control; and (ii) adaptation to a life with chronic pain. The valuing of independence is in line with previous findings. With only three exceptions none of the participants were certain how or where to get help with practical issues and so they lived in fear of loss of their independence. Several sub-categories formed the theme of adaptation. These were acceptance and non-acceptance, pacing oneself, helping other people, the use of prayer and 'looking good and feeling good'. When independence and control is effective, older people may adapt better to chronic pain. CONCLUSION: understanding chronic pain sufferers from their own perspective may have important clinical implications. The interview data informed the development of a booklet designed to meet the needs of older patients with chronic pain.

Predicting spasticity after stroke in those surviving to 12 months.

OBJECTIVE: To measure muscle tone in a cohort of patients 12 months after stroke and develop a preliminary model, using data recorded routinely after stroke, to predict who will develop spasticity. DESIGN: A cohort study. SETTING: Initially hospitalized but subsequently community-dwelling stroke survivors in Liverpool, United Kingdom. SUBJECTS: One hundred and six consecutively presenting stroke patients surviving to 12 months. MAIN OUTCOME MEASURES: Spasticity measured at a range of joints using the Tone Assessment Scale. RESULTS: The Tone Assessment Scale revealed spasticity in 38 (36%) patients and more severe spasticity in 21 (20%) of the 106 patients. Logistic regression analysis revealed that lower day 7 Barthel Index score and early arm or leg weakness were significant predictors of abnormal muscle tone; and lower day 7 Barthel Index score, left-sided weakness and ever smoked to be significant predictors of more severe muscle tone. CONCLUSIONS: Using the models, it may be possible to predict whether or not spasticity will develop in patients 12 months after stroke. The utility of the models is aided by their use of predictor variables that are routinely collected as part of stroke care in hospital and which are easy to measure. The models need testing prospectively in a new cohort of patients in order to test their validity, reliability and utility and to determine if other data could improve their efficiency.

A double-blind randomised placebo-controlled evaluation of three doses of botulinum toxin type A (Dysport) in the treatment of spastic equinovarus deformity after stroke.

BACKGROUND/OBJECTIVES: Calf muscle hypertonicity following stroke may impair walking rehabilitation. The aim of this study was to assess botulinum toxin (Dysport) in post-stroke calf spasticity. METHODS: A prospective, multicentre, double-blind, placebo-controlled, dose-ranging study was performed to evaluate dysport at 500, 1,000 or 1,500 units in 234 stroke patients. They were assessed at 4-week intervals over 12 weeks. RESULTS: The primary outcome measure, 2-min walking distance and stepping rate increased significantly in each group (p < 0.05, paired test), but there was no significant difference between groups (including placebo). Following dysport treatment, there were small but significant (p = 0.0002-0.0188) improvements in calf spasticity, limb pain, and a reduction in the use of walking aids, compared to placebo. Investigators' and patients' assessments of overall benefit suggested an advantage for dysport over placebo, but this was not significant. Sixty-eight patients reported 130 adverse events, with similar numbers in each group. The few severe events recorded were not considered to be treatment-related. CONCLUSION: Dysport resulted in a significant reduction in muscle tone, limb pain and dependence on walking aids. The greatest benefits were in patients receiving dysport 1,500 units, but 1,000 units also had significant effects. Dysport 500 units resulted in some improvements. Since few adverse events were reported, this therapy is considered safe and may be a useful treatment in post-stroke rehabilitation of the leg. Possible reasons why functional improvements in gait parameters were not observed are also discussed.

Prevalence of spasticity post stroke.

OBJECTIVES: To establish the prevalence of spasticity 12 months after stroke and examine its relationship with functional ability. DESIGN: A cohort study of prevalence of spasticity at 12 months post stroke. SETTING: Initially hospitalized but subsequently community-dwelling stroke survivors in Liverpool, UK. SUBJECTS: One hundred and six consecutively presenting stroke patients surviving to 12 months. MAIN OUTCOME MEASURES: Muscle tone measured at the elbow using the Modified Ashworth Scale and at several joints, in the arms and legs, using the Tone Assessment Scale; functional ability using the modified Barthel Index. RESULTS: Increased muscle tone (spasticity) was present in 29 (27%) and 38 (36%) of the 106 patients when measured using the Modified Ashworth Scale and Tone Assessment Scale respectively. Combining the results from both scales produced a prevalence of 40 (38%). Those with spasticity had significantly lower Barthel scores at 12 months (p < 0.0001). CONCLUSION: When estimating the prevalence of spasticity it is essential to assess both arms and legs, using both scales. Despite measuring tone at several joints, spasticity was demonstrated in only 40 (38%) patients, lower than previous estimates.

M-mode ultrasound: a reliable measure of transversus abdominis thickness?

OBJECTIVE: The purpose of this study was to establish a reliable method for measuring transversus abdominis thickness in asymptomatic human subjects in supine lying, standing and walking. DESIGN AND METHODS: This was a single operator reliability study using ultrasound imaging to measure 22 subjects on three separate occasions. A purpose built high-density foam reinforced belt was used to house and position the transducer over the mid-point of the transversus abdominis. Each subject was imaged in supine, standing, and treadmill walking at 3 kph. Intraclass correlation coefficients and standard error of measurement analysis were used to measure the data. RESULTS: The correlation coefficient data analysis resulted in intraclass correlation coefficients of 0.94 (standard error of measurement 0.35) in supine lying, 0.88 (0.66) in standing and 0.88 (0.56) in walking. CONCLUSION: The method described is a reliable tool for measuring changes in thickness of transversus abdominis in supine lying, standing and walking. RELEVANCE: This procedure has the potential to detect dysfunctional changes in abdominal muscle activity for patients with low back pain in a functional setting.

Botulinum toxin A (BoNT-A) for spasticity in adults. What is the evidence?

There are now many reports from open, uncontrolled studies which suggest that botulinum toxin A (BoNT-A) is valuable in treating spasticity. Evidence of its benefit is also gradually accumulating from randomized controlled trials (RCTs). In this presentation I will discuss the reasons why RCT evidence is being generated, and describe the findings currently available, including preliminary results from as yet unpublished trials. RCT data have been reported for leg and arm spasticity in a variety of diseases, but predominantly in stroke and multiple sclerosis patients. In most RCTs, the effects of BoNT-A are compared with placebo over a single injection cycle. The outcomes are generally positive and support the use of BoNT-A. However, data from RCTs are less convincing than those from open studies for a variety of technical reasons. These especially reflect the difficulties of finding good outcome measures for such a heterogeneous array of patients. There is good evidence that BoNT-A has clinical benefit in treating the mechanical effects of spasticity. In order to further clarify its usefulness, future research should address the strategies of short- and longer-term use of BoNT-A, and the unresolved technical issues of how to get the best out of this new treatment.

How effective is the acute low back pain screening questionnaire for predicting 1-year follow-up in patients with low back pain?

OBJECTIVES: The aim of this study was to investigate potential associations between the Acute Low Back Pain Screening Questionnaire (ALBPSQ), a biopsychosocial screening instrument for identifying patients at risk of chronicity, and relevant variables at 1-year follow-up in a cohort of patients with low back pain. STUDY DESIGN: A 1-year prospective study was conducted in which patients who had previously received treatment in the Northern Ireland National Health Service (n = 118) were requested to complete a follow-up questionnaire package of pain and functional disability measures and a patient-centered questionnaire of seven variables considered relevant from the patient's perspective. PATIENTS: Ninety patients (76% response rate) returned the completed questionnaire package. RESULTS: The ALBPSQ total score and cutoff score of 112 were significantly positively associated with the pain and functional disability questionnaire scores at follow-up but did not significantly discriminate for difference scores on these measures. Although six of the seven patient-centered variables were significantly associated with the screening questionnaire total score, the cutoff score was strongly predictive of only one variable (work loss) and failed to demonstrate high levels of sensitivity for other variables (i.e., medication use, additional treatment, poor exercise participation). CONCLUSIONS: The findings of this study demonstrate that scores on the ALBPSQ were positively correlated with patients' levels of pain and functional disability at 1-year follow-up and correctly classified all patients reporting some degree of work loss but had minimal predictive strength for the other patient-centered variables evaluated.

A new, comprehensive normative database of lumbar spine ranges of motion.

AIMS AND OBJECTIVES: To generate gender-specific and broadly based age-related indices for normative lumbar ranges of motion for all planes of movement. DESIGN: This was a repeated measures prospective study of spinal range of motion in a sample of volunteer subjects utilizing a portable modified CA6000 Spine Motion Analyzer (Orthopedic Systems Inc., Union City, CA, USA). SETTING: Data collection was carried out in a variety of community locations including fire, police and ambulance stations, offices and community centres. SUBJECTS: A total of 405 asymptomatic subjects (196 female, 209 male) were recruited, aged 16-90 years, from sedentary, mixed and physically demanding occupations. METHODOLOGY: Indices of lumbar spine ranges of motion were measured in standing following a standardized protocol for sagittal flexion/extension, coronal lateral flexion and horizontal axial rotation movements. RESULTS: Male and female normative flexion ranges declined by approximately 40% (72-40 degrees) across the age spectrum. Extension declined the greatest, by approximately 76% (29-6 degrees) overall. In lateral flexion male and female ranges declined approximately 43% (29-15 degrees) in each direction (total 58-30 degrees). In axial rotation no age-related decline was observed and ranges of motion remained at approximately 7 degrees in each direction (total 14 degrees) across all the ages of the subject group. CONCLUSIONS: Data have been generated that provide comprehensive, gender-specific, broadly based and age-related indices for normative lumbar ranges of motion in all planes of movement. These are applicable to individuals throughout adult life, from adolescence through to old age.