Distinguishing risk of curve progression in adolescent idiopathic scoliosis with bone microarchitecture phenotyping - a 6-year longitudinal study.

Low bone mineral density and impaired bone qualities have been shown to be important prognostic factors for curve progression in Adolescent Idiopathic Scoliosis (AIS). There is no evidence-based integrative interpretation method to analyse high-resolution peripheral quantitative computed tomography (HR-pQCT) data in AIS. This study aimed to (a) utilize unsupervised machine learning to cluster bone microarchitecture phenotypes on HR-pQCT parameters in AIS girls, (b) assess the phenotypes' risk of curve progression and progression to surgical threshold at skeletal maturity (primary cohort), and (c) investigate risk of curve progression in a separate cohort of mild AIS girls whose curve severity did not reach bracing threshold at recruitment (secondary cohort). Patients were followed up prospectively for 6.22 ± 0.33 years in the primary cohort (N = 101). Three bone microarchitecture phenotypes were clustered by Fuzzy C-Means at time of peripubertal peak height velocity (PHV). Phenotype-1 had normal bone characteristics. Phenotype-2 was characterized by low bone volume and high cortical bone density, and Phenotype-3 had low cortical and trabecular bone density and impaired trabecular microarchitecture. The difference in bone qualities amongst the phenotypes was significant at peripubertal PHV and continued to skeletal maturity. Phenotype-3 had significantly increased risk of curve progression to surgical threshold at skeletal maturity (Odd Ratios (OR) = 4.88; 95% Confidence Interval (CI): 1.03-28.63). In the secondary cohort (N = 106), both Phenotype-2 (adjusted OR = 5.39; 95%CI: 1.47-22.76) and Phenotype-3 (adjusted OR = 3.67; 95%CI: 1.05-14.29) had increased risk of curve progression ≥6° with mean follow-up of 3.03 ± 0.16 years. In conclusion, three distinct bone microarchitecture phenotypes could be clustered by unsupervised machine learning on HR-pQCT generated bone parameters at peripubertal PHV in AIS. The bone qualities reflected by these phenotypes were found to have significant differentiating risk of curve progression and progression to surgical threshold at skeletal maturity in AIS.

Adolescent Idiopathic Scoliosis (AIS) is an abnormal spinal curvature commonly presents during puberty growth. Evidence has shown that low bone mineral density and impaired bone qualities are important risk factors for curve progression in AIS. High-resolution peripheral quantitative computed tomography (HR-pQCT) has improved our understanding of bone qualities in AIS. It generates a large amount of quantitative and qualitative bone parameters from a single measurement, but the data are not easy for clinicians to interpret and analyse. This study enrolled AIS girls and used unsupervised machine learning model to analyse their HR-pQCT data at first clinic visit. The model clustered the patients into 3 bone microarchitecture phenotypes (i.e. Phenotype-1: normal, Phenotype-2: low bone volume and high cortical bone density, and Phenotype-3: low cortical and trabecular bone density and impaired trabecular microarchitecture). They were longitudinally followed up for 6 years until skeletal maturity. We observed the three phenotypes were persistent, and Phenotype-3 had a significantly increased risk of curve progression to severity that requires invasive spinal surgery (Odds Ratio = 4.88, P = 0.029). The difference in bone qualities reflected by these 3 distinct phenotypes could aid clinicians to differentiate risk of curve progression and surgery at early stages of AIS.

Clinical Outcomes of 111 Patients with Early Onset Idiopathic Scoliosis (EOIS) Receiving Brace Treatment: A Longitudinal Retrospective Cohort Study.

Introduction: Bracing is one of the first-line treatment for early-onset idiopathic scoliosis (EOIS) to control curves from progression. This study aimed to explore the determinants that govern bracing effectiveness in EOIS. Methods: One hundred and eleven patients with EOIS (mean age of 8.6 ± 1.25 at diagnosis) received bracing treatment and had a final follow-up beyond skeletal maturity were identified from records between 1988 and 2021. Demographic data and clinical features of spinal curvature were obtained for correlation analyses to determine the associations between curve outcomes and clinical features. Results: Most patients were female (85.6%) and had a major curve on the left side (67%). The mean baseline Cobb angle of major curves was 21.73 ± 7.92°, with a mean Cobb angle progression of 18.05 ± 19.11°. The average bracing duration was 5.3 ± 1.9 years. Only 26 (23.4%) of them underwent surgery. The final Cobb angle and curve progression at the final follow-up with a Cobb angle of ≥50° were positively correlated with the initial Cobb angle (r = 0.206 and r = 0.313, respectively) and negatively correlated with maturity parameters. The lumbar curve type was found to correlate with a smaller final Cobb angle. Conclusions: The majority of patients had a final Cobb angle < 50°, which was considered a successful bracing outcome. The final Cobb angle correlated with the initial Cobb angle and curve types observed in EOIS.

Handgrip strength assessment at baseline in addition to bone parameters could potentially predict the risk of curve progression in adolescent idiopathic scoliosis.

Introduction: Adolescent idiopathic scoliosis (AIS) is characterized by deranged bone and muscle qualities, which are important prognostic factors for curve progression. This retrospective case-control study aims to investigate whether the baseline muscle parameters, in addition to the bone parameters, could predict curve progression in AIS. Methods: The study included a cohort of 126 female patients diagnosed with AIS who were between the ages of 12 and 14 years old at their initial clinical visit. These patients were longitudinally followed up every 6 months (average 4.08 years) until they reached skeletal maturity. The records of these patients were thoroughly reviewed as part of the study. The participants were categorized into two sub-groups: the progressive AIS group (increase in Cobb angle of ≥6°) and the stable AIS group (increase in Cobb angle <6°). Clinical and radiological assessments were conducted on each group. Results: Cobb angle increase of ≥6° was observed in 44 AIS patients (34.9%) prior to skeletal maturity. A progressive AIS was associated with decreased skeletal maturity and weight, lower trunk lean mass (5.7%, p = 0.027) and arm lean mass (8.9%, p < 0.050), weaker dominant handgrip strength (8.8%, p = 0.027), deranged cortical compartment [lower volumetric bone mineral density (vBMD) by 6.5%, p = 0.002], and lower bone mechanical properties [stiffness and estimated failure load lowered by 13.2% (p = 0.005) and 12.5% (p = 0.004)]. The best cut-off threshold of maximum dominant handgrip strength is 19.75 kg for distinguishing progressive AIS from stable AIS (75% sensitivity and 52.4% specificity, p = 0.011). Discussion: Patients with progressive AIS had poorer muscle and bone parameters than patients with stable AIS. The implementation of a cut-off threshold in the baseline dominant handgrip strength could potentially be used as an additional predictor, in addition to bone parameters, for identifying individuals with AIS who are at higher risk of experiencing curve progression.

MetaboKit: a comprehensive data extraction tool for untargeted metabolomics.

We have developed MetaboKit, a comprehensive software package for compound identification and relative quantification in mass spectrometry-based untargeted metabolomics analysis. In data dependent acquisition (DDA) analysis, MetaboKit constructs a customized spectral library with compound identities from reference spectral libraries, adducts, dimers, in-source fragments (ISF), MS/MS fragmentation spectra, and more importantly the retention time information unique to the chromatography system used in the experiment. Using the customized library, the software performs targeted peak integration for precursor ions in DDA analysis and for precursor and product ions in data independent acquisition (DIA) analysis. With its stringent identification algorithm requiring matches by both MS and MS/MS data, MetaboKit provides identification results with significantly greater specificity than the competing software packages without loss in sensitivity. The proposed MS/MS-based screening of ISFs also reduces the chance of unverifiable identification of ISFs considerably. MetaboKit's quantification module produced peak area values highly correlated with known concentrations in a DIA analysis of the metabolite standards at both MS1 and MS2 levels. Moreover, the analysis of Cdk1Liv-/- mouse livers showed that MetaboKit can identify a wide range of lipid species and their ISFs, and quantitatively reconstitute the well-characterized fatty liver phenotype in these mice. In DIA data, the MS1-level and MS2-level peak area data produced similar fold change estimates in the differential abundance analysis, and the MS2-level peak area data allowed for quantitative comparisons in compounds whose precursor ion chromatogram was too noisy for peak integration.

Tracking genome-editing and associated molecular perturbations by SWATH mass spectrometry.

Advances in gene editing now allow reverse genetics to be applied to a broad range of biological systems. Ultimately, any modification to coding sequences requires confirmation at the protein level, although immunoblotting is often hampered by antibody quality or availability especially in non-model species. Sequential Window Acquisition of All Theoretical Spectra (SWATH), a mass spectrometry (MS) technology with exceptional quantitative reproducibility and accuracy, offers an ideal alternative for protein-based confirmation. Here, using genome edits in mouse, zebrafish and Bicyclus anynana butterflies produced using either homologous recombination or targeted nucleases, we demonstrate absence of the targeted proteins using SWATH, thus confirming successful editing. We show that SWATH is a robust antibody-independent alternative for monitoring gene editing at the protein level and broadly applicable across diverse organisms and targeted genome manipulation techniques. Moreover, SWATH concomitantly defines the global proteome response in the edited organism, which may provide pertinent biological insights.

Endoscopic Ganglionectomy and Release of the Sixth Extensor Compartment.

Stenosing tenosynovitis of the extensor carpi ulnaris is one of the causes of dorsoulnar wrist pain. Conservative treatment is usually effective to alleviate the pain. Surgical release of the retinaculum of the sixth extensor compartment is indicated if conservative treatment cannot alleviate the pain. The purpose of this Technical Note is to describe the technical details of endoscopic release of the sixth extensor compartment via a 2-portal approach. Endoscopic resection of a ganglion over the sixth compartment can also be performed via the same approach.

Endoscopic Release of Posterior Tibial Tendon Sheath for Stenosing Tenosynovitis of Posterior Tibial Tendon.

Stenosing tenosynovitis of the posterior tibial tendon is a cause of posteromedial ankle pain. Conservative treatment is often ineffective, and surgery is usually required for alleviation of symptoms. Stenosis of the tendon sheath can be overcome by release of the tendon sheath or deepening of the retromalleolar groove. These procedures can be performed endoscopically. The purpose of this Technical Note is to describe the technical details of endoscopic release of the posterior tibial tendon sheath with the advantage of minimal soft tissue dissection and titrated tendon sheath release according to the extent of stenosis. Associated tendon pathology and hindfoot malalignment should be treated accordingly.

SWATH-ID: An instrument method which combines identification and quantification in a single analysis.

Data-independent acquisition (DIA) approaches, such as SWATH® -MS, are showing great potential to reliably quantify significant numbers of peptides and proteins in an unbiased manner. These developments have enhanced interest in developing a single DIA method that integrates qualitative and quantitative analysis, eliminating the need of a prebuilt library of peptide spectra, which are created through data-dependent acquisition methods or from public repositories. Here, we introduce a new DIA approach, referred to as "SWATH-ID," which was developed to allow peptide identification as well as quantitation. The SWATH-ID method is composed of small Q1 windows, achieving better selectivity and thus significantly improving high-confidence peptide extractions from data files. Furthermore, the SWATH-ID approach transmits precursor ions without fragmentation as well as their fragments within the same SWATH acquisition period. This provides a single scan that includes all precursor ions within the isolation window as well as a record of all of their fragment ions, substantially negating the need for a survey scan. In this way all precursors present in a small Q1 window are associated with their fragment ions, improving the identification specificity and providing a more comprehensive and in-depth view of protein and peptide species in complex samples.

Estimating the Cost and Effect of Early Intervention on In-Patient Admission in First Episode Psychosis.

BACKGROUND: Early intervention in psychosis is an accepted policy internationally. When 'A Vision for Change', the national blueprint for mental health policy in Ireland, was published in 2007 there was one Irish pilot service for early intervention in psychosis. The National Clinical Mental Health Programme Plan (2011) identified early intervention in psychosis as one of three areas for roll out nationally. There is limited economic evaluation in the field of mental health in Ireland to guide service development. This is in part due to lack of robust patient level data. AIMS OF THE STUDY: The aim of the study was to investigate whether the introduction of an early intervention service in psychosis resulted in any change to the number and duration of admissions in people with first-episode psychosis. METHODS: We examined two prospective epidemiological cohorts of individuals presenting with first-episode psychosis to an urban community mental health service (population 172,000). The historical cohort comprised of individuals presenting from 1995 to 1998 and received treatment as usual (n=132). The early intervention cohort presented to the same catchment area between 2008 and 2011 (n=97) following the introduction of an early intervention service in 2005. RESULTS: We found significant reductions in the rates admitted for treatment across the two time periods. Reduction in the rate of admission was larger in this catchment than the reduction in the rate of admission in the country as a whole. There were significant reductions in the duration of untreated psychosis arising from the early intervention programme. Significant reductions in length of stay were accounted for by differences in baseline age and marital status. The average cost of admission declined from 15,821 to 9,398 in the early intervention cohort. DISCUSSION AND LIMITATIONS: The comparison pre and post early intervention service showed cost savings consistent with other studies internationally. Key issues are whether changes in the admission pattern were due to the implementation of early intervention or were explained by other factors. Examination of local and national factors showed that the dominant effect was from the implementation of early intervention. Limitations are that this is a comparison with a historical cohort and analysis is limited to in-patient costs only. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE: While there are cost savings, these represent opportunity cost savings, as the majority of costs associated with in-patient care are fixed. Studies such as this provide evidence that it is feasible to consider disinvestment strategies such as home care in the community. IMPLICATIONS FOR HEALTH POLICIES: It is difficult to generalize interventions shown to work in one country to other countries, as health service structures differ and there are both local and national variations in service structure and delivery. It remains important to evaluate whether a policy is applicable within its local context. IMPLICATIONS FOR FURTHER RESEARCH: Further research in this area is required to evaluate contemporaneous services and to examine whether increased costs in the community incurred through implementation of early intervention negate the savings made through reduction of admissions.

Cognitive and symptomatic predictors of functional disability in schizophrenia.

BACKGROUND: Neurocognition and negative symptoms play a major role in predicting functional outcomes in patients with schizophrenia. Few studies have assessed the relationship between functional outcomes and the MATRICS consensus cognition battery (MCCB), which will be central to future clinical trials of cognitive enhancing agents. AIMS: To assess the role of individual MCCB domains on functional outcomes. METHOD: 185 stable outpatients with schizophrenia were enrolled and assessed with the MCCB, Social Adjustment Scale-II (SAS-II) and Multidimensional Scale for Independent Functioning (MSIF), along with BPRS and SANS. RESULTS: We found significant relationships between MCCB neurocognitive domain scores, negative symptoms and aspects of functional outcome in schizophrenia. Specifically, we found that work/education functioning is predicted by working memory performance and negative symptoms; residential status (independent living) is predicted by verbal memory scores; and social functioning is predicted by social cognition, attention and negative symptoms. We also found that negative symptom severity was not related to residential status, even though it demonstrated the predicted associations to work and social functioning. CONCLUSION: To our knowledge, this is the first study to assess cognition and functional outcomes using MCCB, SAS II and MSIF. Our results extend prior work and help provide more data on the relationships between cognition, symptoms and functional outcome using "real world" measures.

The neural correlates of deficient error awareness in attention-deficit hyperactivity disorder (ADHD).

The ability to detect and correct errors is critical to adaptive control of behaviour and represents a discrete neuropsychological function. A number of studies have highlighted that attention-deficit hyperactivity disorder (ADHD) is associated with abnormalities in behavioural and neural responsiveness to performance errors. One limitation of previous work has been a failure to determine the extent to which these differences are attributable to failures of conscious error awareness, a process that is dependent on the integrity of the frontal lobes. Recent advances in electrophysiological research make it possible to distinguish unconscious and conscious aspects of error processing. This study constitutes an extensive electrophysiological investigation of error awareness and error processing in ADHD. A Go/No-Go response inhibition task specifically designed to assess error awareness was administered to a group of adults diagnosed with ADHD and a group of matched control participants. The ADHD group made significantly more errors than the control group but was less likely to consciously detect these errors. An analysis of event-related potentials elicited by errors indicated that an early performance monitoring component (early positivity) was significantly attenuated in the ADHD group as was a later component that specifically reflects conscious error processing (Pe). Dipole source modelling suggested that abnormal Pe amplitudes were attributable to decreased activation of the anterior cingulate cortex. Decreased electrodermal activity in the ADHD group also suggested a motivational insensitivity to performance errors. Our data provide evidence that neuropsychological deficits associated with ADHD can be exacerbated by error processing abnormalities. Error awareness may represent an important cognitive and physiological phenotype for ADHD.

Self-Alert Training: volitional modulation of autonomic arousal improves sustained attention.

The present study examines a new alertness training strategy (Self-Alert Training, SAT) designed to explore the relationship between the top-down control processes governing arousal and sustained attention. In order to maximally target frontal control systems SAT combines a previously validated behavioural self-alerting technique [Robertson, I. H., Tegner, R., Tham, K., Lo, A., & Nimmo-Smith, I. (1995). Sustained attention training for unilateral neglect: Theoretical and rehabilitation implications. Journal of Clinical and Experimental Neuropsychology, 17, 416-430] with an autonomic arousal biofeedback protocol in which participants learn to modulate their own arousal levels. The SAT protocol was first validated with a group of 23 neurologically healthy participants and then independently tested in a group of 18 adults with ADHD to determine its clinical utility. Half of the participants in each group were assigned to a placebo condition to control for non-specific effects. All participants performed the sustained attention to response task (SART) during pre- and post-training testing sessions to assess training effects on sustained attention. By the end of SAT all participants were able to modulate their own arousal levels without external prompting. Comparison of pre- and post-training baseline data indicated that, as predicted, SAT was associated with increased levels of autonomic arousal accompanied by improved accuracy on the SART. In contrast, participants in the placebo condition exhibited a gradual reduction in arousal over time and increased reaction time variability indicative of a vigilance decrement. These data demonstrate that the recruitment of top-down control processes during volitional modulation of arousal leads to improved sustained attention. These findings have important implications for the rehabilitation of attention deficits arising from frontal dysfunction.

Relationship between drug company funding and outcomes of clinical psychiatric research.

BACKGROUND: Pharmaceutical industry funding of psychiatric research has increased significantly in recent decades, raising the question of a relationship between pharmaceutical company funding of clinical psychiatric studies and the outcomes of those studies. This study examines this relationship. METHOD: Abstracts of articles from 1992 and 2002 in four peer-reviewed psychiatric journals were examined. Drug outcomes (n=542) for clinical studies were evaluated and then compared across sponsorship source. Outcome raters were blind to source of sponsorship. The percentage of these studies sponsored by drug companies in 2002 v. 1992 was also compared. In a secondary analysis, the contribution of a series of potentially mediating variables to the relationship between sponsorship source and study outcome was assessed via logistic regression. RESULTS: The percentage of studies sponsored by drug companies increased from 25% in 1992 to 57% in 2002. Favorable outcomes were significantly more common in studies sponsored by the drug manufacturer (78%) than in studies without industry sponsorship (48%) or sponsored by a competitor (28%). These relationships remained after controlling for the effects of journal, year, drug studied, time since FDA drug approval, diagnosis, sample size, and selected study design variables. CONCLUSIONS: These data indicate an association between pharmaceutical industry funding of clinical studies and positive outcomes of those studies. Further research is needed to elucidate the mechanisms underlying this relationship.