Hypertrophic scar therapy : pressure-induced remodelling and its determinents

Hypertrophic scars are cosmetically unattractive products of abnormal wound healing and, if they occur over flexor aspects of joints, considerable functional impairment often results. Pressure, as a therapy for hypertrophic- scarring has considerable attraction since it is effective and nonsurgical. Previous reports of this therapy have not quantified magnitudes or durations of pressure required to induce remodelling. Correlation of these parameters is necessary to define guidelines to optimise pressure therapy. Measurement of pressure applied to hypertrophic scars by garments with elastic properties was achieved using a monitoring system based on a thin (0.2mm) flat (1cm²) capacitive transducer. Pressures of 15 - 40mnmHg produced, in general, accelerated scar remodelling with superior cosmesis resulting from higher pressures. Clinical studies suggested that 6-9 months pressure is sufficient to induce permanent remodelling, although studies of rates of collagen biosynthesis in pressure-treated and untreated scars indicated 9- 12 months pressure was necessary. Two types of pressure applying garments, Tubigrip and Lycra, were studied and compared. Tubigrip garments demonstrated superior elastic properties for maintaining pressure with-time. Investigations of two hypotheses for pressure-induced remodelling were performed. A first hypothesis that pressure induces ischaemia in scars, implying remodelling by autolysis, was investigated with vital microscopy using a hamster cheek pouch model. Pressure magnitudes which induced scar remodelling did not disturb the microcirculation sufficiently to cause permanent damage, therefore this hypothesis was thought unlikely to be correct. A second hypothesis that pressure-induced vascular changes produce scar resorption via a collagen-based mechanism was investigated using a radioactive isotope assay of the rate of collagen biosynthesis. The time for which the rate of collagen biosynthesis approached normal scar levels was reduced by half in pressure-treated compared to untreated scars. A two-phase scar remodelling theory was introduced comprising a pressure-magnitude dependent phase followed by a time-dependent phase. The second hypothesis was thought to be partially correct and the complexity of the pressure-induced remodelling mechanism is discussed.Hypertrophic scars are cosmetically unattractive products of abnormal wound healing and, if they occur over flexor aspects of joints, considerable functional impairment often results. Pressure, as a therapy for hypertrophic- scarring has considerable attraction since it is effective and nonsurgical. Previous reports of this therapy have not quantified magnitudes or durations of pressure required to induce remodelling. Correlation of these parameters is necessary to define guidelines to optimise pressure therapy. Measurement of pressure applied to hypertrophic scars by garments with elastic properties was achieved using a monitoring system based on a thin (0.2mm) flat (1cm²) capacitive transducer. Pressures of 15 - 40mnmHg produced, in general, accelerated scar remodelling with superior cosmesis resulting from higher pressures. Clinical studies suggested that 6-9 months pressure is sufficient to induce permanent remodelling, although studies of rates of collagen biosynthesis in pressure-treated and untreated scars indicated 9- 12 months pressure was necessary. Two types of pressure applying garments, Tubigrip and Lycra, were studied and compared. Tubigrip garments demonstrated superior elastic properties for maintaining pressure with-time. Investigations of two hypotheses for pressure-induced remodelling were performed. A first hypothesis that pressure induces ischaemia in scars, implying remodelling by autolysis, was investigated with vital microscopy using a hamster cheek pouch model. Pressure magnitudes which induced scar remodelling did not disturb the microcirculation sufficiently to cause permanent damage, therefore this hypothesis was thought unlikely to be correct. A second hypothesis that pressure-induced vascular changes produce scar resorption via a collagen-based mechanism was investigated using a radioactive isotope assay of the rate of collagen biosynthesis. The time for which the rate of collagen biosynthesis approached normal scar levels was reduced by half in pressure-treated compared to untreated scars. A two-phase scar remodelling theory was introduced comprising a pressure-magnitude dependent phase followed by a time-dependent phase. The second hypothesis was thought to be partially correct and the complexity of the pressure-induced remodelling mechanism is discussed

Neuropsychological and functional outcomes in recent-onset major depression, bipolar disorder and schizophrenia-spectrum disorders: a longitudinal cohort study

Functional disability is the lead contributor to burden of mental illness. Cognitive deficits frequently limit functional recovery, although whether changes in cognition and disability are longitudinally associated in recent-onset individuals remains unclear. Using a prospective, cohort design, 311 patients were recruited and assessed at baseline. One hundred and sixty-seven patients met eligibility criteria (M = 21.5 years old, s.d. = 4.8) and returned for follow-up (M = 20.6 months later, s.d. = 7.8). Two-hundred and thirty participants were included in the final analysis, comprising clinically stable patients with major depression (n = 71), bipolar disorder (BD; n = 61), schizophrenia-spectrum disorders (n = 35) and 63 healthy controls. Neuropsychological functioning and self-rated functional disability were examined using mixed-design, repeated-measures analysis, across diagnoses and cognitive clusters, covarying for relevant confounds. Clinical, neuropsychological and functional changes did not differ between diagnoses (all P40.05). Three reliable neuropsychological subgroups emerged through cluster analysis, characterized by psychomotor slowing, improved sustained attention, and improved verbal memory. Controlling for diagnosis and changes in residual symptoms, clusters with improved neuropsychological functioning observed greater reductions in functional disability than the psychomotor slowing cluster, which instead demonstrated a worsening in disability (Po0.01). Improved sustained attention was independently associated with greater likelihood of follow-up employment (Po0.01). Diagnosis of BD uniquely predicted both follow-up employment and independent living. Neuropsychological course appears to be independently predictive of subjective and objective functional outcomes. Importantly, cognitive phenotypes may reflect distinct pathophysiologies shared across major psychiatric conditions, and be ideal targets for personalized early intervention

Associations of sNfL with clinico-radiological measures in a large MS population

OBJECTIVE: Evaluation of serum neurofilament light chain (sNfL), measured using high-throughput assays on widely accessible platforms in large, real-world MS populations, is a critical step for sNfL to be utilized in clinical practice. METHODS: Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) is a network of healthcare institutions in the United States and Europe collecting standardized clinical/imaging data and biospecimens during routine clinic visits. sNfL was measured in 6974 MS and 201 healthy control (HC) participants, using a high-throughput, scalable immunoassay. RESULTS: Elevated sNfL levels for age (sNfL-E) were found in 1238 MS participants (17.8%). Factors associated with sNfL-E included male sex, younger age, progressive disease subtype, diabetes mellitus, impaired renal function, and active smoking. Higher body mass index (BMI) was associated with lower odds of elevated sNfL. Active treatment with disease-modifying therapy was associated with lower odds of sNfL-E. MS participants with sNfL-E exhibited worse neurological function (patient-reported disability, walking speed, manual dexterity, and cognitive processing speed), lower brain parenchymal fraction, and higher T2 lesion volume. Longitudinal analyses revealed accelerated short-term rates of whole brain atrophy in sNfL-E participants and higher odds of new T2 lesion development, although both MS participants with or without sNfL-E exhibited faster rates of whole brain atrophy compared to HC. Findings were consistent in analyses examining age-normative sNfL Z-scores as a continuous variable. INTERPRETATION: Elevated sNfL is associated with clinical disability, inflammatory disease activity, and whole brain atrophy in MS, but interpretation needs to account for comorbidities including impaired renal function, diabetes, and smoking

The Sleep Or Mood Novel Adjunctive therapy (SOMNA) trial: a study protocol for a randomised controlled trial evaluating an internet-delivered cognitive behavioural therapy program for insomnia on outcomes of standard treatment for depression in men

BACKGROUND: Insomnia is a significant risk factor for depression onset, can result in more disabling depressive illness, and is a common residual symptom following treatment cessation that can increase the risk of relapse. Internet-based cognitive behavioural therapy for insomnia has demonstrated efficacy and acceptability to men who are less likely than women to seek help in standard care. We aim to evaluate whether internet delivered cognitive behavioural therapy for insomnia as an adjunct to a standard depression therapeutic plan can lead to improved mood outcomes.METHODS/DESIGN: Male participants aged 50 years or more, meeting Diagnostic and Statistical Manual of Mental Disorders criteria for current Major Depressive Episode and/or Dysthymia and self-reported insomnia symptoms, will be screened to participate in a single-centre double-blind randomised controlled trial with two parallel groups involving adjunctive internet-delivered cognitive behavioural therapy for insomnia and an internet-based control program. The trial will consist of a nine-week insomnia intervention period with a six-month follow-up period. During the insomnia intervention period participants will have their depression management coordinated by a psychiatrist using standard guideline-based depression treatments. The study will be conducted in urban New South Wales, Australia, where 80 participants from primary and secondary care and direct from the local community will be recruited. The primary outcome is change in the severity of depressive symptoms from baseline to week 12. DISCUSSION: This study will provide evidence on whether a widely accessible, evidence-based, internet-delivered cognitive behavioural therapy for insomnia intervention can lead to greater improvements than standard treatment for depression alone, in a group who traditionally do not readily access psychotherapy. The study is designed to establish effect size, feasibility and processes associated with implementing e-health solutions alongside standard clinical care, to warrant undertaking a larger more definitive clinical trial.Trial registration: Australian and New Zealand Clinical Trials Registry ACTRN12612000985886.The study is supported by beyondblue: the national depression and anxiety initiative National Priority Driven Research Program and funded through a donation from the Movember Foundation

TarO : a target optimisation system for structural biology

This work was funded by the UK Biotechnology and Biological Sciences Research Council (BBSRC) Structural Proteomics of Rational Targets (SPoRT) initiative, (Grant BBS/B/14434). Funding to pay the Open Access publication charges for this article was provided by BBSRC.TarO (http://www.compbio.dundee.ac.uk/taro) offers a single point of reference for key bioinformatics analyses relevant to selecting proteins or domains for study by structural biology techniques. The protein sequence is analysed by 17 algorithms and compared to 8 databases. TarO gathers putative homologues, including orthologues, and then obtains predictions of properties for these sequences including crystallisation propensity, protein disorder and post-translational modifications. Analyses are run on a high-performance computing cluster, the results integrated, stored in a database and accessed through a web-based user interface. Output is in tabulated format and in the form of an annotated multiple sequence alignment (MSA) that may be edited interactively in the program Jalview. TarO also simplifies the gathering of additional annotations via the Distributed Annotation System, both from the MSA in Jalview and through links to Dasty2. Routes to other information gateways are included, for example to relevant pages from UniProt, COG and the Conserved Domains Database. Open access to TarO is available from a guest account with private accounts for academic use available on request. Future development of TarO will include further analysis steps and integration with the Protein Information Management System (PIMS), a sister project in the BBSRC Structural Proteomics of Rational Targets initiative.Publisher PDFPeer reviewe

Circadian rhythmicity in emerging mood disorders: state or trait marker?

Background: Circadian rhythm disturbances overlap with the symptoms of mood episodes and may trigger or prolong mood symptoms. There is limited research on the role of circadian disturbances in mood disorders in young people and/or first episode cases of unipolar and bipolar disorders. Methods: Actigraphy was undertaken for about 14 days in 63 post-pubertal individuals aged 13–25 years with a recent onset of a mood disorder meeting recognised diagnostic criteria. We examined associations between three easily interpretable markers of circadian rhythm activity (amplitude, acrophase and rhythmicity index) and demography and clinical characteristics. Then, circadian markers were compared between diagnostic groups, controlling for potential confounders. Results: Longer duration of illness was correlated with reduced circadian rhythmicity and lower levels of activity over 24 h. A delay in the timing of maximum activity was associated with the level of manic but not depressive symptoms. The circadian rhythmicity index differentiated unipolar from bipolar cases, and in bipolar but not unipolar disorder, the rhythmicity was less robust in those with more severe manic or depressive symptoms. Conclusions: Less robust circadian rhythmicity, especially associated with increasing symptom severity, may represent a more specific or a trait marker of young people with mood disorders who are at higher risk of a bipolar course of illness

What is the prevalence, and what are the clinical correlates, of insulin resistance in young people presenting for mental health care? A cross-sectional study

Objectives: To report the distribution and predictors of insulin resistance (IR) in young people presenting to primary care-based mental health services. Design: Cross-sectional. Setting: Headspace-linked clinics operated by the Brain and Mind Centre of the University of Sydney. Participants: 768 young people (66% female, mean age 19.7±3.5, range 12–30 years). Main outcome measures: IR was estimated using the updated homeostatic model assessment (HOMA2-IR). Height and weight were collected from direct measurement or self-report for body mass index (BMI). Results: For BMI, 20.6% of the cohort were overweight and 10.2% were obese. However,6.9 mmol/L). By contrast, 9.9% had a HOMA2-IR score \u3e2.0 (suggesting development of IR) and 11.7% (n=90) had a score between 1.5 and 2. Further, there was a positive correlation between BMI and HOMA2-IR (r=0.44, p Conclusions: Emerging IR is evident in a significant subgroup of young people presenting to primary care based mental health services. While the major modifiable risk factor is BMI, a large proportion of the variance is not accounted for by other demographic, clinical or treatment factors. Given the early emergence of IR, secondary prevention interventions may need to commence prior to the development of full-threshold or major mood or psychotic disorders

Subjective memory complaints, vascular risk factors and psychological distress in the middle-aged: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Subjective memory complaints (SMC) are common but their significance is still unclear. It has been suggested they are a precursor of mild cognitive impairment (MCI) or dementia and an early indicator of cognitive decline. Vascular risk factors have an important role in the development of dementia and possibly MCI. We therefore aimed to test the hypothesis that vascular risk factors were associated with SMC, independent of psychological distress, in a middle-aged community-dwelling population.</p> <p>Methods</p> <p>A cross-sectional analysis of baseline data from the 45 and Up Study was performed. This is a cohort study of people living in New South Wales (Australia), and we explored the sample of 45, 532 participants aged between 45 and 64 years. SMC were defined as 'fair' or 'poor' on a self-reported five-point Likert scale of memory function. Vascular risk factors of obesity, diabetes, hypertension, hypercholesterolemia and smoking were identified by self-report. Psychological distress was measured by the Kessler Psychological Distress Scale. We tested the model generated from a randomly selected exploratory sample (n = 22, 766) with a confirmatory sample of equal size.</p> <p>Results</p> <p>5, 479/45, 532 (12%) of respondents reported SMC. Using multivariate logistic regression, only two vascular risk factors: smoking (OR 1.18; 95% CI = 1.03 - 1.35) and hypercholesterolaemia (OR 1.19; 95% CI = 1.04 - 1.36) showed a small independent association with SMC. In contrast psychological distress was strongly associated with SMC. Those with the highest levels of psychological distress were 7.00 (95% CI = 5.41 - 9.07) times more likely to have SMC than the non-distressed. The confirmatory sample also demonstrated the strong association of SMC with psychological distress rather than vascular risk factors.</p> <p>Conclusions</p> <p>In a large sample of middle-aged people without any history of major affective illness or stroke, psychological distress was strongly, and vascular risk factors only weakly, associated with SMC, although we cannot discount psychological distress acting as a mediator in any association between vascular risk factors and SMC. Given this, clinicians should be vigilant regarding the presence of an affective illness when assessing middle-aged patients presenting with memory problems.</p

Derivation of dose/volume constraints for the anorectum from clinician and patient-reported outcomes in the CHHiP trial of radiotherapy fractionation.

BACKGROUND:The CHHiP trial randomised 3216 men with localised prostate cancer (1:1:1) to three radiotherapy fractionation schedules: 74Gy/37 fractions (f) over 7.4 weeks, 60Gy/20f/4 weeks and 57Gy/19f/3.8 weeks. Literature-based dose constraints were applied with arithmetic adjustment for the hypofractionated arms. This study aimed to derive anorectal dose constraints using prospectively-collected clinician-reported outcomes (CRO) and patient-reported outcomes (PRO) and to assess the added predictive value of spatial dose metrics. METHODS:A case-control study design was used, seven CRO and five PRO bowel symptoms were evaluated. Cases experienced a moderate or worse symptom 1-5 years post-radiotherapy, and did not have the symptom pre-radiotherapy. Controls did not experience the symptom at baseline, or between 1-5 years post-radiotherapy. The anorectum was re-contoured from the anal verge to the recto-sigmoid junction; dose/volume parameters were extracted. Univariate logistic regression, atlases of complication indices and bootstrapped receiver-operating-characteristic (ROC) analysis (1000 replicates, balanced outcomes) were used to derive dose constraints for the whole cohort (hypofractionated schedules were converted to 2Gy equivalent schedules using α/β=3Gy) and separate hypofractionated/conventional fractionation cohorts. Only areas under the curve (AUC) with 95% confidence interval lower limits >0.5 were considered statistically significant. Any constraint derived in <95-99% of bootstraps was excluded. RESULTS:Statistically significant dose constraints were derived for CRO, but not PRO. Intermediate to high doses were important for rectal bleeding whereas intermediate doses were important for increased bowel frequency, faecal incontinence and rectal pain. Spatial dose metrics did not improve prediction of CRO or PRO. A new panel of dose constraints for hypofractionated schedules to 60Gy or 57Gy are V20Gy<85%, V30Gy<57%, V40Gy<38%, V50Gy<22% and V60Gy<0.01%. CONCLUSIONS:Dose constraints differed between symptoms, indicating potentially different pathogenesis of radiation-induced side effects. Derived dose constraints were stricter than those used in CHHiP and may reduce bowel symptoms post-radiotherapy