The Effectiveness of Preventative Interventions to Reduce Mental Health Problems in at-risk Children and Young People: A Systematic Review of Reviews.

Mental health problems are the leading cause of childhood disability worldwide, resulting in poor outcomes for children and young people that persist into adulthood. It is essential that those young people most at risk of developing mental health problems receive effective preventative interventions. Whilst there have been a number of systematic reviews which have examined the effectiveness of secondary prevention interventions for specific groups of children and young people, or to address identified mental health concerns, no review has engaged with the breadth of this literature. We conducted a systematic review of systematic reviews to map this complex field of secondary preventative interventions and identify effective interventions to prevent mental health problems in children and adolescents aged 3-17 years. The review protocol was registered on PROSPERO. We searched five electronic databases from inception to February 2023. The certainty of the evidence was appraised using the AMSTAR 2. We included 49 unique systematic reviews each including between 2 and 249 (mean 34) unique studies; the majority of which were reviews which included only or mostly randomised controlled trials (70%). The reviews examined selective interventions (defined as interventions which are delivered to sub-group populations of young people at increased risk of mental health problems) (n = 22), indicated interventions (defined as interventions which target young people who are found to have pre-clinical symptoms) (n = 15) or a synthesis of both (n = 12). The certainty of the evidence in the reviews was rated as high, (n = 12) moderate (n = 5), low (n = 9) and critically low (n = 23). We found evidence to support both selective and indicated interventions in a range of populations and settings, with most of this evidence available for children and young people in their mid-years (6-10 years) and early adolescence (11-13 years). There was a large body of evidence suggesting that resilience enhancing, cognitive behaviour therapy-based and psychoeducational interventions for children who experience adversity, or those with subclinical externalising problems may offer promise. Early selective interventions for a subpopulation of children and young people who have experienced adversity which combines risk reduction and resilience enhancing approaches directed at children and their families may be effective at reducing mental health problems.

Onabotulinum toxin-A (Botox) for spastic equinus in cerebral palsy: a prospective kinematic study.

PURPOSE: Botulinum toxin-A (or Botox) is widely used for the management of equinus gait in children with cerebral palsy but few recent studies have included instrumented gait analysis. METHODS: This was a prospective cohort study. Gait analysis was performed four weeks before and four weeks after Botulinum toxin-A injection for spastic equinus to detect the maximum effects on gait kinematics. Outcome measures included the Gait Profile Score (GPS), the Gait Variable Score (GVS) for the ankle, maximal ankle dorsiflexion and maximal knee extension at midstance. RESULTS: In all, 37 children participated (20 boys); mean age five years seven months (4 years 1 month to 8 years 2 months); 19 with unilateral and 18 bilateral involvement. At a mean four weeks post-injection, the GPS and ankle GVS were unchanged. However maximum ankle dorsiflexion increased for the whole group; median 7.7° (confidence interval (CI) 4° to 10.6°) to 11.5° (CI 7.7° to 12.9°), p = 0.02. Maximum midstance knee extension was unchanged for the whole group, but median knee flexion increased in children with bilateral involvement; 10.9° (CI 7.4° to 20.8°) to 16.5° (CI 8.4° to 19.7°), p = 0.58. CONCLUSION: Injections of the gastrocsoleus for spastic equinus did not result in objective improvements in overall gait. Improvements in ankle dorsiflexion for children with bilateral involvement may be offset by deterioration at the knee. LEVEL OF EVIDENCE: II - prospective cohort study, before and after intervention.

The radiological assessment of pelvic obliquity in cerebral palsy and the impact on hip development.

Pelvic obliquity is a common finding in adolescents with cerebral palsy, however, there is little agreement on its measurement or relationship with hip development at different gross motor function classification system (GMFCS) levels. The purpose of this investigation was to study these issues in a large, population-based cohort of adolescents with cerebral palsy at transition into adult services. The cohort were a subset of a three year birth cohort (n = 98, 65M: 33F, with a mean age of 18.8 years (14.8 to 23.63) at their last radiological review) with the common features of a migration percentage greater than 30% and a history of adductor release surgery. Different radiological methods of measuring pelvic obliquity were investigated in 40 patients and the angle between the acetabular tear drops (ITDL) and the horizontal reference frame of the radiograph was found to be reliable, with good face validity. This was selected for further study in all 98 patients. The median pelvic obliquity was 4° (interquartile range 2° to 8°). There was a strong correlation between hip morphology and the presence of pelvic obliquity (effect of ITDL on Sharpe's angle in the higher hip; rho 7.20 (5% confidence interval 5.59 to 8.81, p < 0.001). This was particularly true in non-ambulant adolescents (GMFCS IV and V) with severe pelvic obliquity, but was also easily detectable and clinically relevant in ambulant adolescents with mild pelvic obliquity. The identification of pelvic obliquity and its management deserves closer scrutiny in children and adolescents with cerebral palsy.

The transverse Vulpius gastrocsoleus recession for equinus gait in children with cerebral palsy.

We report the results of Vulpius transverse gastrocsoleus recession for equinus gait in 26 children with cerebral palsy (CP), using the Gait Profile Score (GPS), Gait Variable Scores (GVS) and movement analysis profile. All children had an equinus deformity on physical examination and equinus gait on three-dimensional gait analysis prior to surgery. The pre-operative and post-operative GPS and GVS were statistically analysed. There were 20 boys and 6 girls in the study cohort with a mean age at surgery of 9.2 years (5.1 to 17.7) and 11.5 years (7.3 to 20.8) at follow-up. Of the 26 children, 14 had spastic diplegia and 12 spastic hemiplegia. Gait function improved for the cohort, confirmed by a decrease in mean GPS from 13.4° pre-operatively to 9.0° final review (p < 0.001). The change was 2.8 times the minimal clinically important difference (MCID). Thus the improvements in gait were both clinically and statistically significant. The transverse gastrocsoleus recession described by Vulpius is an effective procedure for equinus gait in selected children with CP, when there is a fixed contracture of the gastrocnemius and soleus muscles.

The development of Australian Standards of Care for Hip Surveillance in Children with Cerebral Palsy: how did we reach consensus?

Progressive hip displacement is the second most common deformity in children with cerebral palsy (CP). For many decades, the methods of monitoring hip health and development in children with CP varied widely between facilities. Recently, systematic population based studies have identified some of the factors and characteristics of children with CP who would most benefit from hip surveillance. Health services providing hip surveillance within Australia identified a need for clinical guidelines to assist in provision of comprehensive and best practice health care for children with CP across all patient demographics. Guidelines providing clear, evidence based information on specific timing for commencement, frequency, and discharge have not previously been published. This article analyses the supportive evidence for comprehensive hip surveillance, discusses the development of draft guidelines in Australia, and describes the process for achieving national consensus resulting in the Consensus Statement on Hip Surveillance for Children with Cerebral Palsy: Australian Standards of Care. These standards of care are being followed in clinical facilities across Australia and are endorsed by the Australasian Academy of Cerebral Palsy and Developmental Medicine (AusACPDM).

The Consensus Statement on Hip Surveillance for Children with Cerebral Palsy: Australian Standards of Care.

The 'Consensus Statement on Hip Surveillance for Children with Cerebral Palsy: Australian Standards of Care' ('Standards of Care') provides a clear and concise guideline for inclusion of hip surveillance into current services. The 'Standards of Care' have been developed by a multidisciplinary working group for the education and information of all health professionals working with children with CP and their families. The 'Standards of Care' were developed through extensive review of the literature and garnering of expert opinion from professionals working in the area within Australia and New Zealand. A formalized external consensus process was conducted from 2007 to 2008 and the 'Consensus Statement on Hip Surveillance for Children with Cerebral Palsy: Australian Standards of Care' became the basis for best practice around Australia in 2008. It has been endorsed by The Australasian Academy of Cerebral Palsy and Developmental Medicine (AusACPDM). Prospective longitudinal study will evaluate both effectiveness and cost/benefit outcomes of this recommended hip surveillance standard of care.

A randomized controlled trial of the impact of therapeutic horse riding on the quality of life, health, and function of children with cerebral palsy.

This randomized controlled trial examined whether therapeutic horse riding has a clinically significant impact on the physical function, health and quality of life (QoL) of children with cerebral palsy (CP). Ninety-nine children aged 4 to 12 years with no prior horse riding experience and various levels of impairment (Gross Motor Function Classification System Levels I-III) were randomized to intervention (10wks therapeutic programme; 26 males, 24 females; mean age 7y 8mo [SD 2y 5mo] or control (usual activities, 27 males, 22 females; mean age 8y 2mo [SD 2y 6mo]). Pre- and post-measures were completed by 72 families (35 intervention and 37 control). Children's gross motor function (Gross Motor Function Measure [GMFM]), health status (Child Health Questionnaire [CHQ]), and QoL (CP QoL-Child, KIDSCREEN) were assessed by parents and QoL was assessed by children before and after the 10-week study period. On analysis of covariance, there was no statistically significant difference in GMFM, CP QoL-Child (parent report and child self-report), and CHQ scores (except family cohesion) between the intervention and control group after the 10-week study period, but there was weak evidence of a difference for KIDSCREEN (parent report). This study suggests that therapeutic horse riding does not have a clinically significant impact on children with CP. However, a smaller effect cannot be ruled out and the absence of evidence might be explained by a lack of sensitivity of the instruments since the QoL and health measures have not yet been demonstrated to be sensitive to change for children with CP.

Eukaryotic signal transduction via histidine-aspartate phosphorelay.

Transmembrane signal transduction is a feature common to all eukaryotic and prokaryotic cells. We now understand that a subset of the signalling mechanisms used by eukaryotes and prokaryotes are not just similar in principle, but actually use homologous proteins. These are the histidine-aspartate phosphorelays, signalling systems of eubacterial origin, now known to be widespread in eukaryotes outside the animal kingdom. Genome projects are revealing that His-Asp phosphorelays are present as multigene families in lower eukaryotes and in plants. A major challenge is to understand how these 'novel' signal transduction systems form integrated networks with the more familiar signalling mechanisms also present in eukaryotic cells. Already, phosphorelays have been characterised that regulate MAP kinase cascades and the cAMP/PKA pathway. The probable absence of His-Asp phosphorelays from animals has generated interest in their potential as targets for anti-microbial therapy, including antifungals. Recent findings suggest that this approach holds promise.

The RdeA-RegA system, a eukaryotic phospho-relay controlling cAMP breakdown.

The regA and rdeA gene products of Dictyostelium are involved in the regulation of cAMP signaling. The response regulator, RegA, is composed of an N-terminal receiver domain linked to a C-terminal cAMP-phosphodiesterase domain. RdeA may be a phospho-transfer protein that supplies phosphates to RegA. We show genetically that phospho-RegA is the activated form of the enzyme in vivo, in that the predicted site of aspartate phosphorylation is required for full activity. We show biochemically that RdeA and RegA communicate, as evidenced by phospho-transfer between the two proteins in vitro. Phospho-transfer is dependent on the presumed phospho-accepting amino acids, histidine 65 of RdeA and aspartate 212 of RegA, and occurs in both directions. Phosphorylation of RegA by a heterologous phospho-donor protein activates RegA phosphodiesterase activity at least 20-fold. Our results suggest that the histidine phosphotransfer protein, RdeA, and the response regulator, RegA, constitute two essential elements in a eukaryotic His-Asp phospho-relay network that regulates Dictyostelium development and fruiting body maturation.

Taking the plunge. Terminal differentiation in Dictyostelium.

During the last stage of Dictyostelium development a motile, cylindrical slug transforms into an immotile, stalked fruiting body and the constituent cells change from amoebae to either refractile spores or vacuolated stalk cells. Analysis of this process using genetics and simple culture techniques is becoming a powerful way of investigating a number of conserved signal transduction processes. A common pathway activating cAMP-dependent protein kinase (PKA) triggers the maturation of spore cells and those stalk cells forming the stalk. It uses a eukaryotic version of the 'bacterial' two-component phospho-relay system to control cAMP breakdown. A second pathway, inhibiting the GSK3 protein kinase, might control the maturation of a distinct set of stalk cells at the base of the fruiting body.

Evidence that the RdeA protein is a component of a multistep phosphorelay modulating rate of development in Dictyostelium.

We have isolated an insertional mutant of Dictyostelium discoideum that aggregated rapidly and formed spores and stalk cells within 14 h of development instead of the normal 24 h. We have shown by parasexual genetics that the insertion is in the rdeA locus and have cloned the gene. It encodes a predicted 28 kDa protein (RdeA) that is enriched in charged residues and is very hydrophilic. Constructs with the DNA for the c-Myc epitope or for the green fluorescent protein indicate that RdeA is not compartmentalized. RdeA displays homology around a histidine residue at amino acid 65 with members of the H2 module family of phosphotransferases that participate in multistep phosphoryl relays. Replacement of this histidine rendered the protein inactive. The mutant is complemented by transformation with the Ypd1 gene of Saccharomyces cerevisiae, itself an H2 module protein. We propose that RdeA is part of a multistep phosphorelay system that modulates the rate of development.

An intersection of the cAMP/PKA and two-component signal transduction systems in Dictyostelium.

Terminal differentiation of both stalk and spore cells in Dictyostelium can be triggered by activation of cAMP-dependent protein kinase (PKA). A screen for mutants where stalk and spore cells mature in isolation produced three genes which may act as negative regulators of PKA: rdeC (encoding the PKA regulatory subunit), regA and rdeA. The biochemical properties of RegA were studied in detail. One domain is a cAMP phosphodiesterase (Km approximately 5 microM); the other is homologous to response regulators (RRs) of two-component signal transduction systems. It can accept phosphate from acetyl phosphate in a reaction typical of RRs, with transfer dependent on Asp212, the predicted phosphoacceptor. RegA phosphodiesterase activity is stimulated up to 8-fold by the phosphodonor phosphoramidate, with stimulation again dependent on Asp212. This indicates that phosphorylation of the RR domain activates the phosphodiesterase domain. Overexpression of the RR domain in wild-type cells phenocopies a regA null. We interpret this dominant-negative effect as due to a diversion of the normal flow of phosphates from RegA, thus preventing its activation. Mutation of rdeA is known to produce elevated cAMP levels. We propose that cAMP breakdown is controlled by a phosphorelay system which activates RegA, and may include RdeA. Cell maturation should be triggered when this system is inhibited.

A G-protein beta gamma-subunit-responsive phosphoinositide 3-kinase activity in human platelet cytosol.

Thrombin activates phosphoinositide 3-kinase (PI 3-kinase) in platelets via a mechanism involving G-proteins, possibly of both the heterotrimeric and the low molecular weight families. We have investigated the regulation of PI 3-kinase present in platelet cytosol, and we show that this activity can be stimulated by a mixed preparation of G-protein beta gamma-subunits. This stimulation is reversed by preincubation of the beta gamma-subunits with GDP-liganded alpha-subunits. The beta gamma-stimulated activity is inhibited by wortmannin, a recently identified inhibitor of PI 3-kinase in other systems. In addition, the activity associates with PDGF receptor phosphotyrosyl peptide and monoclonal antibody designed to interact with the p85 subunit of PI 3-kinase. We suggest that this beta gamma-sensitive activity is related to previously identified forms of PI 3-kinase.

Solitary colonic metastasis from renal-cell carcinoma 17 years after nephrectomy. Report of a case.

Late recurrence of renal-cell carcinoma can present many years after nephrectomy. To the best of our knowledge, we are reporting the first known case of solitary metastatic renal-cell carcinoma to the colon occurring 17 years after nephrectomy.

Spontaneous rupture of the pulmonary artery.

A 45-year-old man presented with the sudden onset of diaphoresis, generalized weakness, and bilaterally achy arms. Physical examination revealed cyanosis of the head, neck, and upper chest with dyspnea and hypotension. He had distant heart sounds. An upright portable chest radiograph suggested widening of the mediastinum. A right arm venogram was consistent with extrinsic obstruction of the superior vena cava. A computed axial tomography scan demonstrated blood in the pericardium and indistinct widening of the pulmonary outflow tract. Autopsy revealed three tears of the pulmonary artery above the level of valve cusps, and thinning of the artery walls suggested cystic medial necrosis. These findings are suggestive of an acute spontaneous rupture of the pulmonary artery, possibly secondary to cystic medial necrosis.

Isolated dislocation of the proximal tibiofibular joint.

We have reported the case of an anterolateral dislocation of the proximal tibiofibular joint in a soccer player, apparently the second case in the literature. As in that reported by O'Rourke and McManus, this patient was attempting to gain his balance and this may indeed be an important contributing factor. Ogden's classification is now well accepted and has been reviewed along with a discussion of the mechanisms of injury. The diagnosis can generally be made by clinical examination and confirmed by roentgenographs. Treatment usually consists of closed reduction with 3 weeks of casting. In complicated cases, however, resection of the fibular head may be required.

Effects of ischemia on the hind limb of the rat.

The effects of ischemia, induced by a tourniquet, were investigated on 36 adult Holtzman female rates in terms of damage to the ventral horn cell of the spinal cord and tibial nerve and motor end-plate degeneration and regeneration. Clinically, the rats were tested for sensory and motor loss and recovery and these results were compared with the histological findings. Ischemic periods of 2, 4, 6, and 8 hours were used followed by survival times of 3 weeks to 9 months. Histologically, there was degeneration and regeneration found to varying degrees in the nerve and motor end-plate. There were no changes found in the ventral horn cell. There was a loss of pain sensation in all animals, except the 2 hour group, and a loss of motor function. Motor function, preceded by sensation, returned in all animals. With the absence of ventral horn cell damage it was not surprising to find adequate regeneration histologically and, therefore, a return of both sensory and motor function.