Agreement between patient- and proxy-reported outcome measures in adult musculoskeletal trauma and injury: a scoping review.

PURPOSE: Patient-reported outcome measures (PROMs) are widely used in medicine. As older adults, who may rely on a proxy caregiver for answers due to cognitive impairment, are representing an increasing share of the traumatically injured patient population, proxy-reported outcome measures (proxROMs) offer a valuable alternative source of patient-centered information although its association with PROMs is unclear. The objective of this scoping review is to discuss all available literature comparing PROM and proxROMs in adult patients with musculoskeletal trauma to guide future research in this field. METHODS: The PRISMA extension for Scoping Reviews was used to guide this review. MEDLINE, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials were searched without date limit for articles comparing PROM and proxROMs in setting of musculoskeletal trauma. Abstract and full-text screening were performed by two independent reviewers. Variables included study details, patient and proxy characteristics, and reported findings on agreement between PROMs and proxROMs. RESULTS: Of 574 unique records screened, 13 were included. Patient and proxy characteristics varied greatly, while patients' cognitive status and type of proxy perspective were poorly addressed. 18 different PROMs were evaluated, mostly reporting on physical functioning and disability (nine, 50%) or quality of life (six, 33%). Injury- and proxy-specific tools were rare, and psychometric properties of PROMs were often not described. Studies reported moderate to good agreement between PROMs and proxROMs. There is less agreement on subjective outcome measures (e.g., depression score) compared to observable items, and proxy bias results in in worse outcomes compared to patient self-reports. CONCLUSION: Current literature, though limited, demonstrates moderate to good agreement between injured patients' self- and proxy-reports. Future studies should be mindful of current guidelines on proxy reporting when developing their studies and consider including neglected populations such as cognitively impaired patients to improve clinical validity.

Double lesion MRgFUS thalamotomy for essential tremor: 4.5-year outcomes and framework for assessing loss of efficacy and tremor progression.

BACKGROUND: The essential tremor (ET) course to 54 months post-unilateral VIM/PSA magnetic resonance-guided focused ultrasound (MRgFUS) in the treated arm (TA) and non-treated arm (NTA) of 12 patients is reported. METHODS: Tremor severity was rated using Bain Findley spirography (BFS) scores in the TA and NTA. We divided follow-up into 'Early' (0-6 months) and 'Late' (6-54 months) phases, to minimise the effect of peri-lesion oedema resolution on the latter. RESULTS: The mean baseline BFS score was 6.2 in TA and 5.7 in the NTA. After unilateral VIM/PSA MRgFUS, mean BFS improved in TA at all subsequent time points (p < 0.001), with no significant differences between BFS scores at consecutive assessments or between 1 and 54 months, while the NTA BFS scores worsened between 12 and 24 months (p < 0.003). Three patients showed worsening of their TA BFS scores and an increasing NTA-TA BFS difference, indicating slower tremor worsening in TA compared to NTA, whilst one patient showed a greater rate of worsening in the TA compared to NTA BFS. CONCLUSION: After 54 months, the beneficial effect of MRgFUS is usually maintained with any worsening of BFS scores in TA slower than in NTA. Loss of treatment benefit is rare.

Tremor assessment scales before, during and after MRgFUS for essential tremor - results, recommendations and implications.

BACKGROUND: neurosurgical interventions such as MR-guided focused ultrasound (MRgFUS) are increasingly deployed for treatment of essential tremor. OBJECTIVE: to make recommendations for monitoring treatment effects during and after MRgFUS based on our investigation of correlations between different scales of tremor severity. METHODS: twenty-five clinical assessments were collected from thirteen patients before and after unilateral MRgFUS sequential lesioning of the thalamus and posterior subthalamic area for alleviating essential tremor. Scales included Bain Findley Spirography (BFS), Clinical Rating Scale for Tremor (CRST), Upper Extremity Total Tremor Score (UETTS) and Quality of Life of Essential Tremor (QUEST), and were documented at baseline, while lying in the scanner with stereotactic frame attached (BFS), and at 24-month follow-up. RESULTS: the four different scales of tremor severity all correlated significantly. BFS and CRST showed a strong correlation of 0.833 (p < 0.001). BFS, UETTS and CRST correlated moderately with QUEST (ρ = 0.575-0.721, p < 0.001). BFS and UETTS correlated significantly with all CRST subparts, with the strongest correlation between UETTS and CRST part C (ρ = 0.831, p < 0.001). Moreover, BFS drawn sitting upright in an outpatient setting correlated with spirals drawn in a supine position on the scanner bed with the stereotactic frame attached. CONCLUSION: we recommend a combination of BFS & UETTS for intraoperative assessment of awake essential tremor patients and BFS & QUEST for pre-operative and follow-up assessments, as these scale sets are quick and simple to collect and provide meaningful information whilst meeting the practical constraints of intraoperative assessment.

The effect of pedunculopontine nucleus deep brain stimulation on postural sway and vestibular perception.

BACKGROUND AND PURPOSE: Deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) reduces the number of falls in patients with Parkinson's disease (PD). It was hypothesized that enhanced sensory processing contributes to this PPN-mediated gait improvement. METHODS: Four PD patients (and eight matched controls) with implanted bilateral PPN and subthalamic nucleus DBS electrodes were assessed on postural (with/without vision) and vestibular perceptual threshold tasks. RESULTS: Pedunculopontine nucleus ON stimulation (compared to OFF) lowered vestibular perceptual thresholds but there was a disproportionate increase in the normal sway increase on going from light to dark. CONCLUSIONS: The disproportionate increased sway with PPN stimulation in the dark may paradoxically improve balance function since mechanoreceptor signals rapidly adapt to continuous pressure stimulation from postural akinesia. Additionally, the PPN-mediated vestibular signal enhancement also improves the monitoring of postural sway. Overall, PPN stimulation may improve sensory feedback and hence balance performance.

Individual differences in expert motor coordination associated with white matter microstructure in the cerebellum.

Recent investigations into the neural basis of elite sporting performance have focused on whether cortical activity might characterize individual differences in ability. However, very little is understood about how changes in brain structure might contribute to individual differences in expert motor control. We compared the behavior and brain structure of healthy controls with a group of karate black belts, an expert group who are able to perform rapid, complex movements that require years of training. Using 3D motion tracking, we investigated whether the ability to control ballistic arm movements was associated with differences in white matter microstructure. We found that karate experts are better able than novices to coordinate the timing of inter-segmental joint velocities. Diffusion tensor imaging revealed significant differences between the groups in the microstructure of white matter in the superior cerebellar peduncles (SCPs) and primary motor cortex-brain regions that are critical to the voluntary control of movement. Motor coordination, the amount of experience, and the age at which training began were all associated with individual differences in white matter integrity in the cerebellum within the karate groups. These findings suggest a role for the white matter pathways of the SCPs in motor expertise.

Impulse control disorders are associated with lower ventral striatum dopamine D3 receptor availability in Parkinson's disease: A [11C]-PHNO PET study.

INTRODUCTION: Reduced postsynaptic D3 dopaminergic receptor availability has been reported in the ventral striatum of pathological gamblers without Parkinson's disease (PD) and in patients with PD and impulse control disorders (ICD). However, a direct relationship between ventral striatum D3 dopaminergic receptors and the severity of ICD in PD patients has not yet been proven using a validated tool for ICD in PD, such as the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease-Rating Scale (QUIP-RS). In this pilot study, we investigated the relationship between ventral striatum D3 dopamine receptor availability and severity of impulse control disorder (ICD) in Parkinson's disease (PD). METHODS: Twelve patients were assessed with PET and the high affinity dopamine D3 receptor radioligand [11C]-PHNO. Severity of ICD was assessed with the QUIP-RS. RESULTS: We found that lower ventral striatum D3 receptor availability measured with [11C]-PHNO PET was associated with greater severity of ICD, as measured by the QUIP-RS score (rho = -0.625, p = 0.03). CONCLUSION: These findings suggest that the occurrence and severity of ICD in Parkinson's disease may be linked to reductions in ventral striatum dopamine D3 receptor availability. Further studies in larger cohort of patients need to be performed in order to confirm our findings and clarify whether lower ventral striatum D3 receptor may reflect a pharmacological downregulation to higher dopamine release in ventral striatum of patients with ICD or a patients' predisposition to ICD.

Deep brain stimulation: a new treatment for hypertension?

We report a 61-year-old hypertensive man who underwent deep brain stimulation of the periventricular/periaqueductal grey area for the relief of chronic neuropathic pain affecting his oral cavity and soft palate. During intraoperative stimulation, we were able to modulate his blood pressure up or down, depending on electrode location. This is the first evidence that hypertension could be effectively treated with electrical stimulation of the midbrain.

A review of peer-assisted learning to deliver interprofessional supplementary image interpretation skills.

BACKGROUND: Peer-assisted learning provides a means through which individuals can learn from one another through a reciprocal process. Radiographic image interpretation skills are fundamental to both diagnostic radiography students and medical students due to their shared role in preliminary evaluation of conventional radiographic images. Medical students on graduation, may not be well prepared to carry out image interpretation, since evidence suggests that they perform less well than radiographers in e.g. Accident and Emergency situations. METHOD: A review of literature was conducted exploring the application of peer-assisted learning within diagnostic radiography and health education more widely as well as the practice of initial image interpretation. An extensive and systematic search strategy was developed which provided a range of material related to the areas. FINDINGS: An overview was obtained of the effectiveness of peer-assisted learning and the issues associated with development of image interpretation skills and a degree of discrepancy was identified between the two cohorts regarding their interpretative competence and confidence. This inconsistency may create an opportunity to apply peer-assisted learning, better preparing both disciplines for the practical application of image interpretation skills. CONCLUSION: The review identified the lack of a substantial evidence base relating to peer-assisted learning in radiography. Peer-assisted learning is not widely embraced in an interprofessional context. Multiple positive factors of such an intervention are identified which outweigh perceived negative issues. Student teacher and learner may benefit as should the clinical service from enhanced practitioner performance. The findings justify further research to develop the evidence base.

Operative and hardware complications of deep brain stimulation for movement disorders.

The objective of this investigation was to present the operative and hardware complications encountered during follow-up of patients with in situ deep brain stimulators. The study took the form of a retrospective chart review on a series of consecutive patients who were treated successfully with insertion of deep brain stimulators at a single centre by a single surgeon between 1999 and 2005. During the study period, a total of 60 patients underwent 96 procedures for implantation of unilateral or bilateral DBS electrodes. The mean follow-up period was 43.7 months (range 6-78 months) from the time of the first procedure. No patients were lost to follow-up or died. Eighteen patients (30%) developed 28 adverse events, requiring 28 electrodes to be replaced. Seven patients developed two adverse events and two patients developed three adverse events. The rate of adverse events per electrode-year was 8%. We observed a higher proportion of early complications (<6 months postoperatively) in patients with Parkinson's disease, while dystonic patients had more late complications (>6 months postoperatively) and no early complications. Thirty per cent of our patients developed an adverse event that could potentially lead to revision of the implanted hardware. In patients with Parkinson's disease most of the complications tend to occur during the first 6 months postoperatively, while in dystonic patients most occur between 12 and 24 months postoperatively.

Electron microscopy of tissue adherent to explanted electrodes in dystonia and Parkinson's disease.

Deep brain stimulation (DBS) is used to treat a variety of severe medically intractable movement disorders, including Parkinson's disease, tremor and dystonia. There have been few studies examining the effect of chronic DBS on the brains of Parkinson's disease patients. Most of these post mortem studies concluded that chronic DBS caused mild gliosis around the lead track and did not damage brain tissue. There have been no similar histopathological studies on brains from dystonic patients who have undergone DBS. In this study, our objective was to discover whether tissue would be attached to DBS electrodes removed from patients for routine clinical reasons. We hoped that by examining explanted DBS electrodes using scanning (SEM) and/or transmission (TEM) electron microscopy we might visualize any attached tissue and thus understand the electrode-human brain tissue interaction more accurately. Initially, SEM was performed on one control DBS electrode that had not been implanted. Then 21 (one subthalamic nucleus and 20 globus pallidus internus) explanted DBS electrodes were prepared, after fixation in 3% glutaraldehyde, for SEM (n = 9) or TEM (n = 10), or both (n = 2), according to departmental protocol. The electrodes were sourced from two patients with Parkinson's disease, one with myoclonic dystonia, two with cervical dystonia and five with primary generalized dystonia, and had been in situ for 11 and 31 months (Parkinson's disease), 16 months (myoclonic dystonia), 14 and 24 months (cervical dystonia) and 3-24 months (primary generalized dystonia). Our results showed that a foreign body multinucleate giant cell-type reaction was present in all TEM samples and in SEM samples, prewashed to remove surface blood and fibrin, regardless of the diagnosis. Some of the giant cells were >100 microm in diameter and might have originated from either fusion of parenchymal microglia, resident perivascular macrophage precursors and/or monocytes/macrophages invading from the blood stream. The presence of mononuclear macrophages containing lysosomes and sometimes having conspicuous filopodia was detected by TEM. Both types of cell contained highly electron-dense inclusions, which probably represent phagocytosed material. Similar material, the exact nature of which is unknown, was also seen in the vicinity of these cells. This reaction was present irrespective of the duration of implantation and may be a response to the polyurethane component of the electrodes' surface coat. These findings may be relevant to our understanding of the time course of the clinical response to DBS in Parkinson's disease and various forms of dystonia, as well as contributing to the design characteristics of future DBS electrodes.

A novel mouse kidney 3 beta-hydroxysteroid dehydrogenase complementary DNA encodes a 3-ketosteroid reductase instead of a 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase.

The enzyme 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta HSD) is essential for the biosynthesis of all steroid hormones. The enzyme catalyzes the conversion of delta 5-3 beta-hydroxysteroids to delta 4-3-ketosteroids. We report the isolation of a novel mouse 3 beta HSD cDNA, 3 beta HSD IV, and describe the tissue-specific expression of its mRNA, the enzyme characteristics of the 3 beta HSD IV protein, and the structural and functional relationships it has to other 3 beta HSD isoforms previously characterized in the mouse and rat. The predicted amino acid sequence of mouse 3 beta HSD IV is 77% and 73% identical to that of mouse 3 beta HSD I and III, respectively. Comparison of the nucleotide and amino acid sequences of the four isoforms characterized to date show that 3 beta HSD IV is more distantly related to I, II, and III than these three forms are to each other. 3 beta HSD IV mRNA is only expressed in mouse kidney. In situ hybridization of mouse kidney indicates that expression is found only in the cortex and appears to be associated with the proximal tubules. Transiently expressed 3 beta HSD IV protein could not convert the delta 5-3 beta-hydroxysteroids, pregnenolone or dehydroepiandrosterone, to their respective delta 4-3-ketosteroids, progesterone or androstenedione, nor did it have the capacity to convert 5 alpha-androstane-3 beta, 17 beta-diol to dihydrotestosterone, characteristic enzymatic activities of expressed mouse 3 beta HSD I and III. 3 beta HSD IV could only catalyze the conversion of dihydrotestosterone to 5 alpha-androstanediol in the presence of the cofactor NADPH. Thus, 3 beta HSD IV is a 3-ketosteroid reductase rather than a 3 beta-hydroxysteroid dehydrogenase/isomerase despite its homology to the other members of the 3 beta HSD family. Mouse 3 beta HSD IV is functionally and structurally most closely related to rat 3 beta HSD III, an isoform expressed predominantly in male rat liver.

Enzyme characteristics of two distinct forms of mouse 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase complementary deoxyribonucleic acids expressed in COS-1 cells.

The enzyme 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-Isomerase (3 beta HSD) catalyzes the conversion of delta 5-3 beta-hydroxysteroids to delta 4-3-ketosteroids, an essential step in the biosynthesis of all biologically active steroid hormones. We previously reported the isolation of three distinct mouse cDNAs for 3 beta HSD (3 beta HSD I, II, and III) and tissue-specific expression of their mRNAs. 3 beta HSD I is expressed only in gonads and adrenal glands, and 3 beta HSD II and III are expressed in both liver and kidneys. In the current study, we present data which demonstrate that transiently expressed 3 beta HSD I and 3 beta HSD III proteins can catalyze the conversion of the delta 5-steroids, pregnenolone and dehydroepiandrosterone, to their respective delta 4-3-ketosteroids, progesterone and androstenedione. They also can dehydrogenate the 3 beta-hydroxy group of the 5 alpha-reduced steroid 5 alpha-androstanediol to yield dihydrotestosterone in the presence of the cofactor NAD+. The Km values of the expressed 3 beta HSD I (for each of these substrates) were all below 0.2 microM. Km values of 3 beta HSD III were greater for all substrates, with the greatest increase observed for pregnenolone, which was over 10-fold greater. Both forms of expressed protein can catalyze the reduction of dihydrotestosterone to 5 alpha-androstanediol in the presence of the cofactor NADH, but with considerably higher Km values (5.5 microM for form I and 6.8 microM for form III). The observed maximum velocity of form I was much higher for all substrates examined. RNase protection and immunoblot analysis of expressed 3 beta HSD I and III indicate that the difference in maximum velocity reflect differences in the steady state levels of mRNA and amounts of protein. In addition, the expressed 3 beta HSD III protein analyzed by Western blot has a lower mobility than the 3 beta HSD I protein, both similar in mol wt to the 3 beta HSD proteins detected in mouse liver and adrenal glands, respectively. These data demonstrate that an isoform of 3 beta HSD expressed in liver and kidney has the capacity to convert delta 5-3 beta-hydroxysteroids to delta 4-3-ketosteroids. The data suggest that a homologous human 3 beta HSD isoform could play an important role in cases of genetic deficiency of the gonadal and adrenal isoform.

An assessment of disability rating scales used in multiple sclerosis.

Twenty patients with clinically definite, stable multiple sclerosis were examined independently by three of us at the same visit and given scores on the Ambulation Index, Expanded Disability Status Scale, and Kurtzke Functional System scales. Observer error accounted for 12% to 55% of the variation observed between individual Kurtzke Functional System scores, 17.1% of the variation observed between the patients' Expanded Disability Status Scale scores, and only 3.9% of the variation between Ambulation Index scores. The implications of these findings for the choice of scales in clinical trials are described.

Tremor assessment and quality of life measurements.

Essential tremor (ET) can be measured objectively by physiological techniques, simple tests of the tremor's impact on function, or subjective use of clinical rating scales. The methods of measuring ET and its influence on patients are reviewed. Multidimensional evaluations are recommended for the assessment of the severity of ET in clinical trials. The term "detractor" describes the relationships between ET and the disability and handicap that it produces.

Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome.

Intravenous immunoglobulin improves many antibody-mediated autoimmune disorders, but its mode of action is unknown. We investigated its effects on muscle strength and on the serum titer of the calcium-channel autoantibodies that are likely to be pathogenic in the Lambert-Eaton myasthenic syndrome (LEMS). In a randomized, double-blind, placebo-controlled crossover trial, serial indices of limb, respiratory, and bulbar muscle strength and the serum titer of calcium-channel antibodies in nine patients were compared over an 8-week period, using the area-under-the-curve approach, following infusion on two consecutive days of immunoglobulin at 1 g/kg body weight/day (total dose 2.0 g/kg body weight) or placebo (equivalent volume of 0.3% albumin). Calcium-channel antibodies were measured by radioimmunoassay using 125I-omega-conotoxin MVIIC. Direct anti-idiotypic actions of immunoglobulin were tested in this assay. Immunoglobulin infusion was followed by significant improvements in the three strength measures (p = 0.017 to 0.038) associated with a significant decline in serum calcium-channel antibody titers (p = 0.028). Improvement peaked at 2 to 4 weeks and was declining by 8 weeks. Mean serum titers were unchanged at 1 week, however, and direct anti-idiotypic neutralization by immunoglobulin was not demonstrable in vitro. We conclude that immunoglobulin causes a short-term improvement in muscle strength in LEMS that probably results from the induced reduction in calcium-channel autoantibodies. The reduction is not due to a direct neutralizing action of the immunoglobulin, but a delayed anti-idiotypic action cannot be excluded. Improvement following intravenous immunoglobulin in other autoantibody-mediated disorders may similarly be associated with decline in levels of pathogenic autoantibodies.

Effects of the cyclo-oxygenase inhibitor, fenbufen, on clenbuterol-induced hypertrophy of cardiac and skeletal muscle of rats.

1. When rats were fed with clenbuterol for 7 days skeletal muscle mass increased by 21% in the tonic soleus and phasic plantaris muscles and a 16% hypertrophy of the heart was also induced. Fenbufen, fed to rats for the same period, blocked the hypertrophy of the heart but not that of the skeletal muscles. 2. When feeding of fenbufen commenced 3 days before the administration of clenbuterol, plasma prosta-glandin F2 alpha (PGF2 alpha) was reduced by 79%; there was again no effect of fenbufen on clenbuterol-induced increases in the RNA or protein content of plantaris, nor in the increased area of fast or slow twitch fibres in the soleus. In the heart the clenbuterol-induced increases in the RNA (+21%) and protein content (+20%) were totally inhibited. 3. The effects of clenbuterol on heart muscle appear to be mediated by a cyclo-oxygenase metabolite of arachidonic acid whilst the effects on skeletal muscle are not.

The murine 3 beta-hydroxysteroid dehydrogenase multigene family: structure, function and tissue-specific expression.

The classical form of the enzyme 5-ene-3 beta-hydroxysteroid dehydrogenase/isomerase (3 beta HSD), expressed in adrenal glands and gonads, catalyzes the conversion of 5-ene-3 beta-hydroxysteroids to 4-ene-3-ketosteroids, an essential step in the biosynthesis of all active steroid hormones. To date, four distinct mouse 3 beta HSD cDNAs have been isolated and characterized. These cDNAs are expressed in a tissue-specific manner and encode proteins of two functional classes. Mouse 3 beta HSD I and III function as 3 beta-hydroxysteroid dehydrogenases and 5-en-->4-en isomerases using NAD+ as a cofactor. The enzymatic function of 3 beta HSD II has not been completely characterized. Mouse 3 beta HSD IV functions only as a 3-ketosteroid reductase using NADPH as a cofactor. The predicted amino acid sequences of the four isoforms exhibit a high degree of identity. Forms II and III are 85 and 83% homologous to form I. Form IV is most distant from the other three with 77 and 73% sequence identity to I and III, respectively. 3 beta HSD I is expressed in the gonads and adrenal glands of the adult mouse. 3 beta HSD II and III are expressed in the kidney and liver with the expression of form II greater in kidney and form III greater in liver. Form IV is expressed exclusively in the kidney. Although the amino acid composition of forms I, III and IV predicts proteins of the same molecular weight, the proteins have different mobilities on SDS-polyacrylamide gel electrophoresis. This characteristic allows for differential identification of the expressed proteins. The four structural genes encoding the different isoforms are closely linked within a segment of mouse chromosome 3 that is conserved on human chromosome 1.