Precision computerised cognitive behavioural therapy (cCBT) for adolescents with depression: a pilot and feasibility randomised controlled trial protocol for SPARX-UK.

BACKGROUND: A serious game called SPARX (Smart, Positive, Active, Realistic, X-factor thoughts), originally developed in New Zealand and incorporating cognitive behavioural therapy (CBT) principles, has been shown to help reduce symptoms of depression and anxiety in adolescents with mild to moderate depression in studies undertaken in Australasia. However, SPARX has never been trialled in the United Kingdom (UK), and there have been issues relating to low engagement when it has been used in a real-world context. AIMS: To conduct the first pilot and feasibility randomised controlled trial (RCT) in England to explore the use of SPARX in different settings. The trial will explore whether SPARX supported by an e-coach (assistant psychologists) improves adherence and engagement compared with self-directed (i.e. self-help) use. The trial results will be used to inform the optimal mode of delivery (SPARX supported vs. SPARX self-directed), to calculate an appropriate sample size for a full RCT, and to decide which setting is most suitable. METHODS: Following consultation with young people to ensure study suitability/appropriateness, a total of 120 adolescents (11-19 years) will be recruited for this three-arm study. Adolescents recruited for the study across England will be randomised to receive either SPARX with human support (from an e-coach), self-directed SPARX, or a waitlist control group. Assessments will be conducted online at baseline, week 4, and 8-10-week post-randomisation. The assessments will include measures which capture demographic, depression (Patient Health Questionnaire modified for adolescents [PHQ-A]) and anxiety (Revised Child Anxiety and Depression Scale [RCADS]) symptomatology, and health-related quality-of-life data (EQ-5D-Y and proxy version). Analyses will be primarily descriptive. Qualitative interviews will be undertaken with a proportion of the participants and clinical staff as part of a process evaluation, and the qualitative data gathered will be thematically analysed. Finally, feasibility data will be collected on recruitment details, overall study uptake and engagement with SPARX, participant retention, and youth-reported acceptability of the intervention. DISCUSSION: The findings will inform the design of a future definitive RCT of SPARX in the UK. If the subsequent definitive RCT demonstrates that SPARX is effective, then an online serious game utilising CBT principles ultimately has the potential to improve the provision of care within the UK's health services if delivered en masse. TRIAL REGISTRATION: ISRCTN: ISRCTN15124804. Registered on 16 January 2023, https://www.isrctn.com/ISRCTN15124804 .

Modified realist evaluation of a complex, multi-centred, multi-intervention programme.

Well North was a complex, multi-intervention health improvement programme spanning 10 sites across the North of England. The aim was to address inequalities by improving the health of the poorest fastest, increasing resilience and reducing levels of worklessness. The intention of the programme was for all sites to have freedom and flexibility to conduct different interventions reflecting local priorities. Evaluation ran concurrently with the programme, and an iterative approach was required to ensure constant feedback, allowing the programme to be adapted and improved as necessary. Realist methodology was chosen for evaluation, as it provides insight into what works, for whom and in what circumstances. Due to the complex nature of the programme and diverse approaches, it was necessary to adapt the methodology to meet the needs of the evaluation. The Evaluation Team utilized a range of qualitative and quantitative techniques within the context of a Rapid Cycle Evaluation framework. For each project, Contexts, Mechanisms and Outcomes (CMOs) were identified at three stages and were incorporated into the CMO configuration, leading to the development of a middle range theory. Validation and testing of theory took place at every stage. Realist methodology was the most appropriate existing method. However, it still necessitated modification.

A systematic review and meta-analysis of risk factors associated with healthcare-associated infections among hospitalized patients in Chinese general hospitals from 2001 to2022.

BACKGROUND: Healthcare-associated infections (HAIs) are a serious global public health issue. However, a comprehensive analysis of risk factors for HAIs has yet been undertaken at a large scale among general hospitals in China. The aim of this review was to assess risk factors associated with HAIs in Chinese general hospitals. METHODS: Medline, EMBASE and Chinese Journals Online databases were searched to find studies published from 1st January 2001 to 31st May 2022. The random-effects model was used to estimate odds ratio (OR). Heterogeneity was assessed based on the τˆ2 and I2 statistics. RESULTS: A total of 5037 published papers were identified from the initial search and 58 studies were included in the quantitative meta-analysis; 1,211,117 hospitalized patients were incorporated covering 41 regions in 23 provinces of China and 29,737 were identified as having HAIs. Our review showed that HAIs were significantly associated with sociodemographic characteristics including age older than 60 years (OR: 1.74 (1.38-2.19)) and male sex (1.33 (1.20-1.47)); invasive procedures (3.54 (1.50-8.34)); health conditions such as chronic diseases (1.49 (1.22-1.82)), coma (OR: 5.12 (1.70-15.38)) and immunosuppression (2.45 (1.55-3.87)). Other risk factors included long-term bed (5.84 (5.12-6.66)), and healthcare-related risk factors such as chemotherapy (1.96 (1.28-3.01)), haemodialysis (3.12 (1.80-5.39)), hormone therapy (2.96(1.96-4.45)), immunosuppression (2.45 (1.55-3.87)) and use of antibiotics (6.64 (3.16-13.96)), and longer than 15 hospitalization days (13.36 (6.80-26.26)). CONCLUSIONS: Being male and aged over 60 years, invasive procedure, health conditions, healthcare-related risk factors, and longer than 15 hospitalization days were the main risk factors associated with HAIs in Chinese general hospitals. This supports the evidence base to inform the relevant cost-effective prevention and control strategies.

A systematic review and meta-analysis of disease burden of healthcare-associated infections in China: an economic burden perspective from general hospitals.

Healthcare-associated infections (HAIs) are a global public health issue. However, the economic burden attributable to HAIs at a national level is unknown in China. The aim of this systematic review was to estimate the direct economic burden caused by HAIs in China. Medline, EMBASE and Chinese Journals Online databases were searched, including studies published from 2009 to 2019. The pooled estimates with 95% confidence interval were calculated with quantile estimation. The random effects model of the DerSimonian-Laird method was used. The statistical significance was set as P<0.05. A total of 2756 publications were identified; six studies were included in a meta-analysis to calculate the pooled estimates of direct economic burden, while five were included in the pooled estimates of the additional economic burden. The pooled median estimates of the total medical expenditure, the medicine expenditure and hospitalization days per inpatient of patients with HAIs were ¥34,415.62, ¥20,065.21 and 34.01 days, respectively (P<0.0001). The pooled median estimates of the differences of the total medical expenditure, the medicine expenditure and hospitalization days per inpatient between patients with HAIs and patients without HAIs were ¥24,881.37, ¥9,438.46 and 13.89 days, respectively (P<0.01). In conclusion, the cost of care for patients with HAIs was significantly higher than that for those without HAIs. This excess economic burden is likely to impact on patients and their families as well as health service providers and the healthcare system as a whole. Effective surveillance systems and cost-effective interventions are needed to control HAIs.

Suppressor of cytokine signaling 3 (SOCS3) limits damage-induced crypt hyper-proliferation and inflammation-associated tumorigenesis in the colon.

Intestinal injury or chronic inflammation induce cytokines that promote crypt regeneration and mucosal repair. If excessive or prolonged, such mechanisms may increase colon cancer risk. Factors that terminate or limit cytokine action in intestinal epithelial cells (IEC) may protect against crypt hyperplasia and neoplasia. We hypothesized that suppressor of cytokine signaling-3 (SOCS3) is such a factor. Mice with Vilin-promoter/Cre-recombinase (VC)-mediated IEC-specific SOCS3 gene disruption (VC/HO), WT/HO littermates with floxed but intact SOCS3 genes and VC/WT mice were studied. Colon was examined after acute dextran sodium sulfate (DSS)-induced mucosal injury or after azoxymethane (AOM) and chronic DSS. Signaling pathways were examined in colon, cultured IEC or colon cancer cell lines. VC/HO mice showed no basal phenotype. After acute DSS, VC/HO exhibited enhanced crypt proliferation and crypt hyperplasia and reduced transforming growth factor (TGF) beta expression in colon. Inflammation and mucosal damage were similar across genotypes. Following AOM/DSS, VC/HO mice had increased size, number and load of colonic tumors and increased STAT3 and nuclear factor-kappa B (NF-kappaB) activation in colon. In vitro, SOCS3 overexpression reduced proliferation, IL-6-mediated STAT3 activation and tumor necrosis factor (TNF) alpha-mediated NF-kappaB activation. We conclude that cytokine induction of SOCS3 normally provides an intrinsic mechanism to limit injury-induced crypt hyperproliferation and inflammation-associated colon cancer by regulating both STAT3 and NF-kappaB pathways.

A virtual reality surgery simulation of cutting and retraction in neurosurgery with force-feedback.

A virtual-reality surgical simulator aimed at neurosurgery is presented. The simulator utilises boundary element (BE) technology to develop real-time realistic deformable models of the brain. The simulator incorporates the simulation of surgical prodding, pulling and cutting. Advanced features include the separation the cut surfaces by retractors and post-cutting deformations. The experience of virtual surgery is enhanced by implementing 3D stereo-vision and the use of two hand-held force-feedback devices.

Rapid loss of Oct-4 and pluripotency in cultured rodent blastocysts and derivative cell lines.

The POU transcription factor Oct-4 is essential for the pluripotent character of the mouse inner cell mass (ICM) and derivative embryonic stem (ES) cells. We analyzed the expression of Oct-4 during culture and establishment of cell lines from mouse and rat preimplantation embryos. Oct-4 was rapidly lost in primary outgrowths of the majority of cultured embryos prior to any evidence of morphological differentiation. Oct-4 persisted in only a minority of strain 129 cultures, which can go on to give ES cells. We used transgenic rats in which the dual reporter/selection marker beta-geo is under control of Oct-4 regulatory elements to investigate the effect of direct selection for Oct-4 expressing cells. Ablation of all cells occurred, consistent with complete downregulation of Oct-4. Without selection, in contrast, continuous cultures of morphologically undifferentiated cells could be derived readily from rat blastocysts and ICMs. However, these cells did not express significant Oct-4 and, although capable of differentiating into extraembryonic cell types, appeared incapable of producing fetal germ layer derivatives. Downregulation of Oct-4 appears to be a limiting factor in attempts to derive pluripotent cell lines from preimplantation embryos.

The SOCS box of suppressor of cytokine signaling-1 is important for inhibition of cytokine action in vivo.

Suppressor of Cytokine Signaling-1 (SOCS-1) is an essential physiological inhibitor of IFN-gamma signaling. Mice lacking this gene die in the early postnatal period from a disease characterized by hyperresponsiveness to endogenous IFN-gamma. The SOCS box is a C-terminal domain shared with over 30 other proteins that links SOCS proteins to an E3 ubiquitin ligase activity and the proteasome, but whether it contributes to inhibition of cytokine signaling is currently disputed. We have deleted only the SOCS box of the SOCS-1 gene in mice and show that such mice have an increased responsiveness to IFN-gamma and slowly develop a fatal inflammatory disease. These results demonstrate that deletion of the SOCS box leads to a partial loss of function of SOCS-1.

Negative regulation of cytokine signaling.

Cytokines use complex signaling cascades to elicit their biological effects, many of which involve phosphorylation as a mechanism of activation. Rapid and efficient attenuation of cytokine signals is crucial to maintaining regulation of these processes and to preventing toxic side effects. Phosphatases have been shown to be involved in these regulatory processes, but more recent research has seen the discovery of two new families of negative regulators, the suppressor of cytokine signaling (SOCS) and protein inhibitors of signal transducer and activator of transcription (STAT) (PIAS) protein families. SOCS proteins are induced by and inhibit many cytokine-signaling systems in a classic negative-feedback loop, and the generation of transgenic and knockout models has greatly increased our understanding of their physiological functions. PIAS proteins interact with the transcriptional mediators of cytokine action, the STATs, to suppress their DNA-binding activity. These three classes of molecules form what is now emerging as an integrated system for deactivating cytokine signaling at a number of levels, from the receptor to the transcription factor.

The suppressors of cytokine signaling (SOCS) proteins: important feedback inhibitors of cytokine action.

While positive effectors of cytokine signaling pathways are relatively well defined, negative regulation can be just as important but is poorly understood. The recently discovered suppressor of cytokine signaling (SOCS) family of proteins has been implicated in the negative regulation of several cytokine pathways, particularly the receptor-associated tyrosine kinase/signal transducer and activator of transcription (AK/STAT) pathways of transcriptional activation. Biochemical studies revealed that inhibition can occur via a variety of mechanisms. SOCS proteins bind to tyrosine-phosphorylated residues of target proteins via their SH2 domains, then inhibit JAK activity through their N-terminal domains, and are thought to induce degredation of bound molecules through a conserved SOCS-box motif that interacts with the proteasome. SOCS protein expression is induced by a wide variety of cytokines with each member displaying varying kinetics of induction. Gene modification studies in mice have demonstrated that SOCS-1 has a clear role in the negative regulation of interferon-gamma signaling, while other SOCS family members have also been shown to be involved in the regulation of T cell, growth hormone, and erythropoietin signaling systems.

Gigantism in mice lacking suppressor of cytokine signalling-2.

Suppressor of cytokine signalling-2 (SOCS-2) is a member of the suppressor of cytokine signalling family, a group of related proteins implicated in the negative regulation of cytokine action through inhibition of the Janus kinase (JAK) signal transducers and activators of transcription (STAT) signal-transduction pathway. Here we use mice unable to express SOCS-2 to examine its function in vivo. SOCS-2(-/-) mice grew significantly larger than their wild-type littermates. Increased body weight became evident after weaning and was associated with significantly increased long bone lengths and the proportionate enlargement of most organs. Characteristics of deregulated growth hormone and insulin-like growth factor-I (IGF-I) signalling, including decreased production of major urinary protein, increased local IGF-I production, and collagen accumulation in the dermis, were observed in SOCS-2-deficient mice, indicating that SOCS-2 may have an essential negative regulatory role in the growth hormone/IGF-I pathway.

The organization of a galectin gene from Teladorsagia circumcincta.

Galectins are a family of soluble beta-galactoside-binding lectins that are conserved amongst a broad range of organisms. We have previously isolated cDNA clones coding for galectins from the sheep gastrointestinal nematode parasites Teladorsagia circumcincta, Haemonchus contortus and Trichostrongylus colubriformis, revealing a high level of identity between these molecules. This subsequent study reports the organization of the T. circumcincta Tci-gal-1 galectin gene. The coding region is broken into eight exons covering 6.6 kbp, with introns ranging in size from 55 base pairs (bp) to 2.8 kbp. Comparisons with recently reported galectin structures from Caenorhabditis elegans reveal strong architectural similarity between galectins from the parasitic and free-living nematodes, but this structure is not conserved in mammalian galectins.

Recombinant expression of a galectin from the sheep gastrointestinal parasite Teladorsagia circumcincta: its use in isolating galectin-glycoconjugates.

Galectins, or beta-galactoside-binding lectins, are a family of proteins that have been described in vertebrates and, more recently, invertebrates, including nematode parasites. A tandem repeat-type galectin from the sheep gastrointestinal parasite, Teladorsagia circumcincta, has previously been isolated and the cDNA cloned. This molecule and each of its domains were expressed as fusion proteins with glutathione S-transferase (GST). The full-length molecule and the C-terminal domain were expressed in soluble form and the purified fusion proteins demonstrated a capacity to bind beta-galactoside sugars, with the greatest preference for lactose. The full-length fusion protein was used to successfully isolate potential galectin-glycoconjugates from within the parasite and from sheep serum.

cDNA cloning of galectins from third stage larvae of the parasitic nematode Teladorsagia circumcincta.

A monoclonal antibody raised to a Teladorsagia circumcincta 31-33 kDa doublet antigen was used to immunoscreen a T. circumcincta cDNA expression library. Sheep antibodies eluted from the proteins expressed by two clones immunopositive with the monoclonal antibody specifically recognised the doublet antigen on Western blots of third stage larval extract, confirming that these clones coded for the antigen. Database searches revealed high levels of similarity with beta-galactoside-binding lectin-like proteins (Ga1BPs or galectins) from Caenorhabditis elegans and Onchocerca volvulus. By analogy with these sequences, both T. circumcincta cDNA clones contain the full-length protein coding region. The native doublet proteins could be preferentially extracted from homogenates of third stage larvae with lactose and could be affinity purified on an asialofetuin column, confirming the identity of these bands as galectins. Reverse transcriptase-polymerase chain reaction amplification using a primer based on the C. elegans Spliced Leader SL1 sequence showed that the corresponding T. circumcincta mRNAs are also trans-spliced at their 5' ends. While there are considerable nucleotide differences between the two clones, the majority are located in the non-coding regions. Within the coding region there are 87 nucleotide differences but only three of these result in amino acid substitutions.

An in vivo mammary infusion model for tissue migration of leucocytes during inflammation.

Infusion of LPS or nematode larvae into the mammary glands of sheep induces recruitment of neutrophils or eosinophils respectively. While neutrophil recruitment required only a single infusion of LPS, repeated infusions of parasite larvae were required to induce significant eosinophil migration into the lumen of the glands. Eosinophil recruitment was accompanied by a distinct population of lymphocytes consisting mainly of activated (MHC class II and CD25+) T cells. L-selectin was expressed at reduced levels on both neutrophils and eosinophils collected from the mammary gland compared with cells present in the blood of the same sheep. In addition, VLA-4 and beta 1-integrin were down-regulated or negative in mammary eosinophils compared with strong expression in the blood while neutrophils were negative for these markers in both mammary washes and blood. Eosinophils in blood and mammary glands were negative for MHC class II, CD25 and CD4. Mast cells and lymphocyte aggregates were present in the tissue of glands chronically stimulated with parasite larvae while eosinophils were only present if the gland had been recently stimulated. These studies show that detailed in vivo analysis of leucocyte migration can be easily performed in the sheep mammary infusion model which allows non-invasive and repeated sampling of inflammatory cells before and after tissue migration.

Respiratory arrest in a parturient following intrathecal injection of sufentanil and bupivacaine.

A 19-year-old obstetric patient had a respiratory arrest shortly after receiving intrathecal sufentanil and bupivacaine as part of a combined epidural/spinal technique for pain relief in labour.