Search

While decision analysis has the potential to improve treatment decisions, the quality of patient specific data has hindered its development. Experience with the General Practice Research Database (GPRD) indicated the possibility of generating such data. The example developed concerns the probability of recurrent stroke and the risks and benefits of treatment with aspirin. Eight criteria were systematically applied to identify suitable patients from the 664,241 cohort of patients in the West Midlands GPRD. The risk of recurrent stroke was estimated using survival analysis, yielding multivariate hazard ratios for 960 patient profiles. These were used to populate a decision analysis model. The study highlights how decision analysis can introduce evidence-based information into the consultation. Data can be transformed into information for the increasingly complex world of general practice. This can clarify the risks and benefits of prescribing, assist GP--patient dialogue and promote shared decision-making. [ABSTRACT FROM AUTHOR]

Introduction and Aims: Digital biomarkers can provide a cost-effective, objective and robust measure for neurological disease progression, changes in care needs and the effect of interventions. Motor function, physiology and behaviour can provide informative measures of neurological conditions and neurodegenerative decline. New digital technologies present an opportunity to provide remote, high-frequency monitoring of patients from within their homes. The purpose of the living lab study is to develop novel digital biomarkers of functional impairment in those living with neurodegenerative disease (NDD) and neurological conditions., Methods and Analysis: The Living Lab study is a cross-sectional observational study of cognition and behaviour in people living with NDDs and other, non-degenerative neurological conditions. Patients (n≥25 for each patient group) with dementia, Parkinson's disease, amyotrophic lateral sclerosis, mild cognitive impairment, traumatic brain injury and stroke along with controls (n≥60) will be pragmatically recruited. Patients will carry out activities of daily living and functional assessments within the Living Lab. The Living Lab is an apartment-laboratory containing a functional kitchen, bathroom, bed and living area to provide a controlled environment to develop novel digital biomarkers. The Living Lab provides an important intermediary stage between the conventional laboratory and the home. Multiple passive environmental sensors, internet-enabled medical devices, wearables and electroencephalography (EEG) will be used to characterise functional impairments of NDDs and non-NDD conditions. We will also relate these digital technology measures to clinical and cognitive outcomes., Ethics and Dissemination: Ethical approvals have been granted by the Imperial College Research Ethics Committee (reference number: 21IC6992). Results from the study will be disseminated at conferences and within peer-reviewed journals., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Key Points: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder of motor neurons, carrying a short survival. High-density motor unit recordings permit analysis of motor unit size (amplitude) and firing behaviour (afterhyperpolarization duration and muscle fibre conduction velocity). Serial recordings from biceps brachii indicated that motor units fired faster and with greater amplitude as disease progressed. First-recruited motor units in the latter stages of ALS developed characteristics akin to fast-twitch motor units, possibly as a compensatory mechanism for the selective loss of this motor unit subset. This process may become maladaptive, highlighting a novel therapeutic target to reduce motor unit vulnerability., Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with a median survival of 3 years. We employed serial high-density surface electromyography (HDSEMG) to characterize voluntary and ectopic patterns of motor unit (MU) firing at different stages of disease. By distinguishing MU subtypes with variable vulnerability to disease, we aimed to evaluate compensatory neuronal adaptations that accompany disease progression. Twenty patients with ALS and five patients with benign fasciculation syndrome (BFS) underwent 1-7 assessments each. HDSEMG measurements comprised 30 min of resting muscle and 1 min of light voluntary activity from biceps brachii bilaterally. MU decomposition was performed by the progressive FastICA peel-off technique. Inter-spike interval, firing pattern, MU potential area, afterhyperpolarization duration and muscle fibre conduction velocity were determined. In total, 373 MUs (ALS = 287; BFS = 86) were identified from 182 recordings. Weak ALS muscles demonstrated a lower mean inter-spike interval (82.7 ms) than strong ALS muscles (96.0 ms; P = 0.00919) and BFS muscles (95.3 ms; P = 0.0039). Mean MU potential area (area under the curve: 487.5 vs. 98.7 μV ms; P < 0.0001) and muscle fibre conduction velocity (6.2 vs. 5.1 m/s; P = 0.0292) were greater in weak ALS muscles than in BFS muscles. Purely fasciculating MUs had a greater mean MU potential area than MUs also under voluntary command (area under the curve: 679.6 vs. 232.4 μV ms; P = 0.00144). These results suggest that first-recruited MUs develop a faster phenotype in the latter stages of ALS, likely driven by the preferential loss of vulnerable fast-twitch MUs. Inhibition of this potentially maladaptive phenotypic drift may protect the longevity of the MU pool, stimulating a novel therapeutic avenue., (© 2021 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Studies show conflicting results on whether exercise interventions to improve outcomes for women with breast cancer are cost-effective. We modelled the long-term cost-effectiveness of the Exercise for Health intervention compared with usual care. A lifetime Markov cohort model for women with early breast cancer was constructed taking a societal perspective. Data were obtained from trial, epidemiological, quality of life, and healthcare cost reports. Outcomes were calculated from 5000 Monte Carlo simulations, and one-way and probabilistic sensitivity analyses. Over the cohort's remaining life, the incremental cost for the exercise versus usual care groups were $7409 and quality-adjusted life years (QALYs) gained were 0.35 resulting in an incremental cost per QALY ratio of AU$21,247 (95% Uncertainty Interval (UI): Dominant, AU$31,398). The likelihood that the exercise intervention was cost-effective at acceptable levels was 93.0%. The incremental cost per life year gained was AU$8894 (95% UI Dominant, AU$11,769) with a 99.4% probability of being cost effective. Findings were most sensitive to the probability of recurrence in the exercise and usual care groups, followed by the costs of out-of-pocket expenses and the model starting age. This exercise intervention for women after early-stage breast cancer is cost-effective and would be a sound investment of healthcare resources.

Delayed diagnosis of amyotrophic lateral sclerosis prevents early entry into clinical trials at a time when neuroprotective therapies would be most effective. Fasciculations are an early hallmark of amyotrophic lateral sclerosis, preceding muscle weakness and atrophy. To assess the potential diagnostic utility of fasciculations measured by high-density surface electromyography, we carried out 30-min biceps brachii recordings in 39 patients with amyotrophic lateral sclerosis, 7 patients with benign fasciculation syndrome, 1 patient with multifocal motor neuropathy and 17 healthy individuals. We employed the surface potential quantification engine to compute fasciculation frequency, fasciculation amplitude and inter-fasciculation interval. Inter-group comparison was assessed by Welch's analysis of variance. Logistic regression, receiver operating characteristic curves and decision trees discerned the diagnostic performance of these measures. Fasciculation frequency, median fasciculation amplitude and proportion of inter-fasciculation intervals <100 ms showed significant differences between the groups. In the best-fit regression model, increasing fasciculation frequency and median fasciculation amplitude were independently associated with the diagnosis of amyotrophic lateral sclerosis. Fasciculation frequency was the single best measure predictive of the disease, with an area under the curve of 0.89 (95% confidence interval 0.81-0.98). The cut-off of more than 14 fasciculation potentials per minute achieved 80% sensitivity (95% confidence interval 63-90%) and 96% specificity (95% confidence interval 78-100%). In conclusion, non-invasive measurement of fasciculation frequency at a single time-point reliably distinguished amyotrophic lateral sclerosis from its mimicking conditions and healthy individuals, warranting further research into its diagnostic applications., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Myoclonus describes a movement disorder characterised by brief, abrupt and involuntary contractions of muscles or groups of muscles, usually associated with intracranial lesions, with limited evidence linking it to spinal pathologies. The pathophysiology of spinal myoclonus is extensive and multifactorial. Infection, intramedullary and extramedullary space-occupying lesions, trauma, vascular abnormalities, degenerative processes and cervical spondylosis have been implicated with the disease, the latter been associated with cervical stenosis with no reported cases linking it to an underlying cervical disc herniation. Although medical therapy with clonazepam, levetiracetam, valproate, tetrabenazine hydrochloride and spinal block injections has been equivocal, spinal myoclonus secondary to disc herniation requires surgical intervention. This report describes a case of segmental spinal myoclonus, secondary to a herniated cervical intervertebral disc. After corpectomy and a cage-augmented fusion technique, the myoclonic symptoms resolved. To our knowledge, this was the first report to describe the successful management of discogenic spinal myoclonus with spinal surgery., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: AL amyloidosis and multiple myeloma result in extracellular deposition of insoluble fibrillary protein in tissue and organs. Untreated median survival is very poor, and even worse with cardiac involvement. Chemotherapy and peripheral blood stem cell transplantation (PBSCT) have been shown to dramatically improve survival, with hematologic remission documented. Regression of cardiac changes has previously been shown, as assessed by echocardiography (TTE) and cardiac magnetic resonance imaging (CMR). This study is a comparison of TTE and CMR in long-term survivors of cardiac amyloidosis with regression., Results: Four long-term survivors with cardiac amyloidosis and regression of cardiac features on TTE were identified. Mean age was 60 years and average survival was 139 months from the time of diagnosis of cardiac involvement. Statistically significant regression of the cardiac features of cardiac amyloidosis were demonstrated on TTE. In these survivors, post-PBSCT structural assessments were similar between TTE and CMR. Classical strain imaging features of cardiac amyloidosis were only present in 50%. All patients had diffuse, patchy gadolinium enhancement on CMR after PBSCT., Conclusions: Treatment of cardiac amyloidosis with chemotherapy and PBSCT may result in regression of abnormalities on TTE with marked improvement in survival. Post treatment, TTE and CMR structural assessments appear similar. Gadolinium imaging suggests that microscopic residual infiltration persists despite macroscopic regression. Significant cardiac improvements with prolonged survival are seen nonetheless. Multimodality imaging has a vital role in the management of cardiac amyloidosis.

Objectives: although melatonin prescribing in England has been increasing in recent years, there have been no large scale studies on the safety of melatonin compared to other medical treatments for insomnia. The primary aim of this study was to examine the association between exposure to melatonin, hypnotic benzodiazepines (temazepam, nitrazepam) or Z-drugs (zolpidem, zopiclone) and fracture risk., Design: retrospective cohort study., Setting: 309 general practices contributing to The Health Improvement Network (THIN) between 2008 and 2013., Participants: 1,377 patients aged 45 years and older prescribed melatonin; 880 patients prescribed hypnotic benzodiazepines; 1,148 patients prescribed Z-drugs and 2,752 unexposed controls matched by age, gender and practice., Main Outcome: fracture following prescription of study drugs ascertained from practice records., Results: the unadjusted hazard ratios for fracture during the follow-up period were 1.90 (95% CI 1.41-2.57) for melatonin, 1.70 (95% CI 1.18-2.46) for hypnotic benzodiazepines and 2.03 (95% CI 1.45-2.84) for Z-drugs. After adjustment for 26 covariates, the hazard ratios were 1.44 (95% CI 1.01-2.04) for melatonin, 1.26 (95% CI 0.82-1.92) for hypnotic benzodiazepines and 1.52 (95% CI 1.04-2.23) for Z-drugs. Only patients with three or more melatonin prescriptions had elevated risk. The mean time to fracture was 1.04 years and there was no significant difference in mean time to fracture between the cohorts., Conclusions: in this large cohort of patients attending UK primary care, prescriptions for melatonin and Z-drugs were associated with a significantly increased risk of fracture. With the use of melatonin increasing steadily overtime, this study adds to the literature on the safety profile of this drug., (© The Author 2016. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

A case report highlighting a rare and striking, but perhaps under-recognized, cause of reported sleep-talking to a specialist sleep clinic, involving "gas-lighting" by the bed partner., (© 2015 American Academy of Sleep Medicine.)

Background: While weight gain following breast cancer is considered common, results supporting these findings are dated. This work describes changes in body weight following breast cancer over 72 months, compares weight with normative data and explores whether weight changes over time are associated with personal, diagnostic, treatment or behavioral characteristics., Methods: A population-based sample of 287 Australian women diagnosed with early-stage invasive breast cancer was assessed prospectively at six, 12, 18 and 72 months post-surgery. Weight was clinically measured and linear mixed models were used to explore associations between weight and participant characteristics (collected via self-administered questionnaire). Those with BMI changes of one or more units were considered to have experienced clinically significant changes in weight., Results: More than half (57%) of participants were overweight or obese at 6 months post-surgery, and by 72 months post-surgery 68% of women were overweight or obese. Among those who gained more weight than age-matched norms, clinically significant weight gain between 6 and 18 months and 6 and 72 months post-surgery was observed in 24% and 39% of participants, respectively (median [range] weight gain: 3.9 kg [2.0-11.3 kg] and 5.2 kg [0.6-28.7], respectively). Clinically-significant weight losses were observed in up to 24% of the sample (median [range] weight loss between 6 and 72 months post-surgery: -6.4 kg [-1.9--24.6 kg]). More extensive lymph node removal, being treated on the non-dominant side, receiving radiation therapy and lower physical activity levels at 6 months was associated with higher body weights post-breast cancer (group differences >3 kg; all p < 0.05)., Conclusions: While average weight gain among breast cancer survivors in the long-term is small, subgroups of women experience greater gains linked with adverse health and above that experienced by age-matched counterparts. Weight change post-breast cancer is a contemporary public health issue and the integration of healthy weight education and support into standard breast cancer care has potential to significantly improve the length and quality of cancer survivorship.

Sentences were reduced to an array of sixteen effectively rectangular bands (RBs) having center frequencies ranging from 0.25 to 8 kHz spaced at ⅓-octave intervals. Four arrays were employed, each having uniform subcritical bandwidths which ranged from 40 Hz to 5 Hz. The 40 Hz width array had intelligibility near ceiling, and the 5 Hz array about 1%. The finding of interest was that when the subcritical speech RBs were used to modulate RBs of noise having the same center frequency as the speech but having bandwidths increased to a critical (ERBn) bandwidth at each center frequency, these spectrally smeared arrays were considerably more intelligible in all but the 40 Hz (ceiling) condition. For example, when the 10 Hz bandwidth speech array having an intelligibility of 8% modulated the ERBn noise array, intelligibility increased to 48%. This six-fold increase occurred despite elimination of spectral fine structure and addition of stochastic fluctuation to speech envelope cues. (As anticipated, conventional vocoding with matching bandwidths of speech and noise reduced the 10-Hz-speech array intelligibility from 8% to 1%). These effects of smearing confirm findings by Bashford, Warren, and Lenz (2010) that optimal temporal processing requires stimulation of a critical bandwidth. [Supported by NIH].

While broadband speech may remain perfectly intelligible at levels exceeding 90 dB, narrowband speech intelligibility (e.g., 2/3-octave passband centered at 1.5 kHz) may decline by 25% or more at moderate intensities (e.g., 75 dB). This "rollover" effect is substantially reduced, however, when a speech band is accompanied by flanking bands of white noise [J.A. Bashford, R.M. Warren, & P.W. Lenz, 2005, J. Acoust. Soc. Am. 117, 365-369 (2005)], suggesting that lateral suppression helps preserve broadband speech intelligibility at high levels. The present study found that when noise flankers were presented individually at a low spectrum level (-30 dB relative to the speech) only the higher-frequency flanker produced a significant intelligibility increase. However, the lower-frequency flanking noise did produce an equivalent increase when its spectrum level was raised 10 dB. This asymmetrical intensity requirement for noise flankers links the effective dynamic range of speech intelligibility to reported characteristics of both lateral (two-tone) suppression of auditory nerve (AN) fiber activity and lateral inhibition of secondary cells of the cochlear nucleus. These and other observations will be discussed in the broader context of how various auditory mechanisms help preserve speech intelligibility at high intensities by reducing firing rate saturation. [Supported by NIH.].

The treatment of acute promyelocytic leukemia has improved considerably after recognition of the effectiveness of all-trans-retinoic acid (ATRA), anthracycline-based chemotherapy, and arsenic trioxide (ATO). Here we report the use of all 3 agents in combination in an APML4 phase 2 protocol. For induction, ATO was superimposed on an ATRA and idarubicin backbone, with scheduling designed to exploit antileukemic synergy while minimizing cardiotoxicity and the severity of differentiation syndrome. Consolidation comprised 2 cycles of ATRA and ATO without chemotherapy, followed by 2 years of maintenance with ATRA, oral methotrexate, and 6-mercaptopurine. Of 124 evaluable patients, there were 4 (3.2%) early deaths, 118 (95%) hematologic complete remissions, and all 112 patients who commenced consolidation attained molecular complete remission. The 2-year rate for freedom from relapse is 97.5%, failure-free survival 88.1%, and overall survival 93.2%. These outcomes were not influenced by FLT3 mutation status, whereas failure-free survival was correlated with Sanz risk stratification (P[trend] = .03). Compared with our previously reported ATRA/idarubicin-based protocol (APML3), APML4 patients had statistically significantly improved freedom from relapse (P = .006) and failure-free survival (P = .01). In conclusion, the use of ATO in both induction and consolidation achieved excellent outcomes despite a substantial reduction in anthracycline exposure. This trial was registered at the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) as ACTRN12605000070639.

The structure of the contact network between individuals has a profound effect on the transmission of infectious disease. Using a novel technology--proximity sensing radio collars--we described the contact network in a population of Tasmanian devils. This largest surviving marsupial carnivore is threatened by a novel infectious cancer. All devils were connected in a single giant component, which would permit disease to spread throughout the network from any single infected individual. Unlike the contact networks for many human diseases, the degree distribution was not highly aggregated. Nevertheless, the empirically derived networks differed from random networks. Contact networks differed between the mating and non-mating seasons, with more extended male-female associations in the mating season and a greater frequency of female-female associations outside the mating season. Our results suggest that there is limited potential to control the disease by targeting highly connected age or sex classes.

The value of administering sequential courses of chemotherapy containing high-dose cytarabine in both induction and consolidation therapy for acute myeloid leukemia (AML) has not been assessed in a prospective randomized trial. Two hundred ninety-two AML patients aged 15 to 60 years were enrolled in the Australasian Leukaemia and Lymphoma Group (ALLG) AML trial number 7 (M7) protocol to evaluate this question. All received induction therapy with the ICE protocol (idarubicin 9 mg/m2 x 3; cytarabine 3 g/m2 twice a day on days 1, 3, 5, 7; etoposide 75 mg/m2 x 7). Complete remission was achieved in 234 (80%) patients. Two hundred two patients in remission were then randomized to either a further identical cycle of ICE or 2 attenuated courses (cytarabine 100 mg/m2 daily x 5, idarubicin x 2, etoposide x 5 [IcE]). ICE consolidation therapy was more toxic than IcE, however, the treatment-related death rate was not significantly different. There was no difference between the 2 consolidation arms for relapse-free survival at 3 years (49% for ICE vs 46% for IcE; P = .66), survival following randomization (61% vs 62%; P = .91), or the cumulative incidence of relapse (43% vs 51%; P = .31), and there was no difference within cytogenetic risk groups. Intensive induction chemotherapy incorporating high-dose cytarabine results in high complete remission rates, but further intensive consolidation treatment does not appear to confer additional benefit.

Introduction: Computerised decision support systems are increasingly important in primary care for the practice of evidence-based medicine and the development of shared GP-patient decision making. However, despite their emergence, such systems have not been entirely embraced by GPs. There is little qualitative research exploring practical barriers to the adoption of decision support systems in this setting., Method: Qualitative interviews with 15 GPs in the West Midlands., Results: Several practical barriers were identified to the use of computerised support systems in primary care consultations. These included limitations of practitioners' IT skills, problems for GPs in understanding the risk output of systems and GP concerns about communicating risk sufficiently well to patients. Concerns over the time implications of using a system in a consultation was also identified as a barrier., Conclusion: Designers of decision support systems for use in primary care consultations must account for the practical needs of users when developing computerised support systems. Systems must be acceptable to the format of a consultation, include definitions of what output means, and help facilitate dialogue between the GP and the patient.