Summary Background Trial findings show cognitive behaviour therapy (CBT) and graded exercise therapy (GET) can be effective treatments for chronic fatigue syndrome, but patients' organisations have ...reported that these treatments can be harmful and favour pacing and specialist health care. We aimed to assess effectiveness and safety of all four treatments. Methods In our parallel-group randomised trial, patients meeting Oxford criteria for chronic fatigue syndrome were recruited from six secondary-care clinics in the UK and randomly allocated by computer-generated sequence to receive specialist medical care (SMC) alone or with adaptive pacing therapy (APT), CBT, or GET. Primary outcomes were fatigue (measured by Chalder fatigue questionnaire score) and physical function (measured by short form-36 subscale score) up to 52 weeks after randomisation, and safety was assessed primarily by recording all serious adverse events, including serious adverse reactions to trial treatments. Primary outcomes were rated by participants, who were necessarily unmasked to treatment assignment; the statistician was masked to treatment assignment for the analysis of primary outcomes. We used longitudinal regression models to compare SMC alone with other treatments, APT with CBT, and APT with GET. The final analysis included all participants for whom we had data for primary outcomes. This trial is registered at http://isrctn.org , number ISRCTN54285094. Findings We recruited 641 eligible patients, of whom 160 were assigned to the APT group, 161 to the CBT group, 160 to the GET group, and 160 to the SMC-alone group. Compared with SMC alone, mean fatigue scores at 52 weeks were 3·4 (95% CI 1·8 to 5·0) points lower for CBT (p=0·0001) and 3·2 (1·7 to 4·8) points lower for GET (p=0·0003), but did not differ for APT (0·7 −0·9 to 2·3 points lower; p=0·38). Compared with SMC alone, mean physical function scores were 7·1 (2·0 to 12·1) points higher for CBT (p=0·0068) and 9·4 (4·4 to 14·4) points higher for GET (p=0·0005), but did not differ for APT (3·4 −1·6 to 8·4 points lower; p=0·18). Compared with APT, CBT and GET were associated with less fatigue (CBT p=0·0027; GET p=0·0059) and better physical function (CBT p=0·0002; GET p<0·0001). Subgroup analysis of 427 participants meeting international criteria for chronic fatigue syndrome and 329 participants meeting London criteria for myalgic encephalomyelitis yielded equivalent results. Serious adverse reactions were recorded in two (1%) of 159 participants in the APT group, three (2%) of 161 in the CBT group, two (1%) of 160 in the GET group, and two (1%) of 160 in the SMC-alone group. Interpretation CBT and GET can safely be added to SMC to moderately improve outcomes for chronic fatigue syndrome, but APT is not an effective addition. Funding UK Medical Research Council, Department of Health for England, Scottish Chief Scientist Office, Department for Work and Pensions.
A multi-centre, four-arm trial (the PACE trial) found that rehabilitative cognitive behaviour therapy (CBT) and graded exercise therapy (GET) were more effective treatments for chronic fatigue ...syndrome (CFS) than specialist medical care (SMC) alone, when each was added to SMC, and more effective than adaptive pacing therapy (APT) when added to SMC. In this study we compared how many participants recovered after each treatment.
We defined recovery operationally using multiple criteria, and compared the proportions of participants meeting each individual criterion along with two composite criteria, defined as (a) recovery in the context of the trial and (b) clinical recovery from the current episode of the illness, however defined, 52 weeks after randomization. We used logistic regression modelling to compare treatments.
The percentages (number/total) meeting trial criteria for recovery were 22% (32/143) after CBT, 22% (32/143) after GET, 8% (12/149) after APT and 7% (11/150) after SMC. Similar proportions met criteria for clinical recovery. The odds ratio (OR) for trial recovery after CBT was 3.36 95% confidence interval (CI) 1.64–6.88 and for GET 3.38 (95% CI 1.65–6.93), when compared to APT, and after CBT 3.69 (95% CI 1.77–7.69) and GET 3.71 (95% CI 1.78–7.74), when compared to SMC (p values < or =0.001 for all comparisons). There was no significant difference between APT and SMC. Similar proportions recovered in trial subgroups meeting different definitions of the illness.
This study confirms that recovery from CFS is possible, and that CBT and GET are the therapies most likely to lead to recovery.
The developing brain undergoes systematic changes that occur at successive stages of maturation. Deviations from the typical neurodevelopmental trajectory are hypothesized to underlie many early ...childhood disorders; thus, characterizing the earliest patterns of normative brain development is essential. Recent neuroimaging research provides insight into brain structure during late childhood and adolescence; however, few studies have examined the infant brain, particularly in infants under 3 months of age. Using high-resolution structural MRI, we measured subcortical gray and white matter brain volumes in a cohort (
N
= 143) of 1-month infants and examined characteristics of these volumetric measures throughout this early period of neurodevelopment. We show that brain volumes undergo age-related changes during the first month of life, with the corresponding patterns of regional asymmetry and sexual dimorphism. Specifically, males have larger total brain volume and volumes differ by sex in regionally specific brain regions, after correcting for total brain volume. Consistent with findings from studies of later childhood and adolescence, subcortical regions appear more rightward asymmetric. Neither sex differences nor regional asymmetries changed with gestation-corrected age. Our results complement a growing body of work investigating the earliest neurobiological changes associated with development and suggest that asymmetry and sexual dimorphism are present at birth.
Objective: To re-examine the standard pNN50 heart rate variability (HRV) statistic by determining how other thresholds compare with the commonly adopted 50 ms threshold in distinguishing ...physiological and pathological groups. Design: Retrospective analysis of Holter monitor databases. Subjects: Comparison of HRV data between 72 healthy subjects and 43 with congestive heart failure (CHF); between sleeping and waking states in the 72 healthy subjects; and between 20 young and 20 healthy elderly subjects. Main outcome measures: Probability values for discriminating between groups using a family of pNN values ranging from pNN4 to pNN100. Results: For all three comparisons, pNN values substantially less than 50 ms consistently provided better separation between groups. For the normal versus CHF groups, p < 10−13 for pNN12 versus p < 10−4 for pNN50; for the sleeping versus awake groups, p < 10−21 for pNN12 versus p < 10−10 for pNN50; and for the young versus elderly groups, p < 10−6 for pNN28 versus p < 10−4 for pNN50. In addition, for the subgroups of elderly healthy subjects versus younger patients with CHF, p < 0.007 for pNN20 versus p < 0.17 for pNN50; and for the subgroup of New York Heart Association functional class I–II CHF versus class III–IV, p < 0.04 for pNN10 versus p < 0.13 for pNN50. Conclusions: pNN50 is only one member of a general pNNx family of HRV statistics. Enhanced discrimination between a variety of normal and pathological conditions is obtained by using pNN thresholds as low as 20 ms or less rather than the standard 50 ms threshold.
Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder resulting in selective neuronal loss and dysfunction in the striatum and cortex. The molecular pathways ...leading to the selectivity of neuronal cell death in HD are poorly understood. Proteolytic processing of full-length mutant huntingtin (Htt) and subsequent events may play an important role in the selective neuronal cell death found in this disease. Despite the identification of Htt as a substrate for caspases, it is not known which caspase(s) cleaves Htt in vivo or whether regional expression of caspases contribute to selective neuronal cells loss. Here, we evaluate whether specific caspases are involved in cell death induced by mutant Htt and if this correlates with our recent finding that Htt is cleaved in vivo at the caspase consensus site 552. We find that caspase-2 cleaves Htt selectively at amino acid 552. Further, Htt recruits caspase-2 into an apoptosome-like complex. Binding of caspase-2 to Htt is polyglutamine repeat-length dependent, and therefore may serve as a critical initiation step in HD cell death. This hypothesis is supported by the requirement of caspase-2 for the death of mouse primary striatal cells derived from HD transgenic mice expressing full-length Htt (YAC72). Expression of catalytically inactive (dominant-negative) forms of caspase-2, caspase-7, and to some extent caspase-6, reduced the cell death of YAC72 primary striatal cells, while the catalytically inactive forms of caspase-3, -8, and -9 did not. Histological analysis of post-mortem human brain tissue and YAC72 mice revealed activation of caspases and enhanced caspase-2 immunoreactivity in medium spiny neurons of the striatum and the cortical projection neurons when compared to controls. Further, upregulation of caspase-2 correlates directly with decreased levels of brain-derived neurotrophic factor in the cortex and striatum of 3-month YAC72 transgenic mice and therefore suggests that these changes are early events in HD pathogenesis. These data support the involvement of caspase-2 in the selective neuronal cell death associated with HD in the striatum and cortex.
White matter microstructure, essential for efficient and coordinated transmission of neural communications, undergoes pronounced development during the first years of life, while deviations to this ...neurodevelopmental trajectory likely result in alterations of brain connectivity relevant to behavior. Hence, systematic evaluation of white matter microstructure in the normative brain is critical for a neuroscientific approach to both typical and atypical early behavioral development. However, few studies have examined the infant brain in detail, particularly in infants under 3 months of age. Here, we utilize quantitative techniques of diffusion tensor imaging and neurite orientation dispersion and density imaging to investigate neonatal white matter microstructure in 104 infants. An optimized multiple b-value diffusion protocol was developed to allow for successful acquisition during non-sedated sleep. Associations between white matter microstructure measures and gestation corrected age, regional asymmetries, infant sex, as well as newborn growth measures were assessed. Results highlight changes of white matter microstructure during the earliest periods of development and demonstrate differential timing of developing regions and regional asymmetries. Our results contribute to a growing body of research investigating the neurobiological changes associated with neurodevelopment and suggest that characteristics of white matter microstructure are already underway in the weeks immediately following birth.
High-quality evidence is lacking for the impact on healthcare utilisation of short-stay alternatives to psychiatric inpatient services for people experiencing acute and/or complex mental health ...crises (known in England as psychiatric decision units PDUs). We assessed the extent to which changes in psychiatric hospital and emergency department (ED) activity were explained by implementation of PDUs in England using a quasi-experimental approach.
We conducted an interrupted time series (ITS) analysis of weekly aggregated data pre- and post-PDU implementation in one rural and two urban sites using segmented regression, adjusting for temporal and seasonal trends. Primary outcomes were changes in the number of voluntary inpatient admissions to (acute) adult psychiatric wards and number of ED adult mental health-related attendances in the 24 months post-PDU implementation compared to that in the 24 months pre-PDU implementation.
The two PDUs (one urban and one rural) with longer (average) stays and high staff-to-patient ratios observed post-PDU decreases in the pattern of weekly voluntary psychiatric admissions relative to pre-PDU trend (Rural: -0.45%/week, 95% confidence interval CI = -0.78%, -0.12%; Urban: -0.49%/week, 95% CI = -0.73%, -0.25%); PDU implementation in each was associated with an estimated 35-38% reduction in total voluntary admissions in the post-PDU period. The (urban) PDU with the highest throughput, lowest staff-to-patient ratio and shortest average stay observed a 20% (-20.4%, CI = -29.7%, -10.0%) level reduction in mental health-related ED attendances post-PDU, although there was little impact on long-term trend. Pooled analyses across sites indicated a significant reduction in the number of voluntary admissions following PDU implementation (-16.6%, 95% CI = -23.9%, -8.5%) but no significant (long-term) trend change (-0.20%/week, 95% CI = -0.74%, 0.34%) and no short- (-2.8%, 95% CI = -19.3%, 17.0%) or long-term (0.08%/week, 95% CI = -0.13, 0.28%) effects on mental health-related ED attendances. Findings were largely unchanged in secondary (ITS) analyses that considered the introduction of other service initiatives in the study period.
The introduction of PDUs was associated with an immediate reduction of voluntary psychiatric inpatient admissions. The extent to which PDUs change long-term trends of voluntary psychiatric admissions or impact on psychiatric presentations at ED may be linked to their configuration. PDUs with a large capacity, short length of stay and low staff-to-patient ratio can positively impact ED mental health presentations, while PDUs with longer length of stay and higher staff-to-patient ratios have potential to reduce voluntary psychiatric admissions over an extended period. Taken as a whole, our analyses suggest that when establishing a PDU, consideration of the primary crisis-care need that underlies the creation of the unit is key.
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