The SECURE STAIRS Framework: Preliminary Evaluation of Trauma Informed Training Developments Within the Children and Young People's Secure Estate.

The SECURE STAIRS framework promotes trauma informed understanding and training across the workforce to inform work with children and young people. A component of the framework is the 'Trauma Informed Practice with Children and Young People in Secure Settings' (TIPSS) training programme for multidisciplinary staff. Between November 2020 and May 2021, a total of 123 members of multidisciplinary staff from a Secure Children's Home (SCH) in the North East of England attended five-day TIPSS training. A pre-post repeated measures design was adopted. Paired samples t-tests were used to analyse pre- and post- questionnaires regarding self-reported levels of (i) knowledge, (ii) understanding and (iii) confidence across Attachment and Developmental Trauma, Understanding Complex Behaviour and Trauma Informed Care training modules. Staff reported significant (p ≤ .001) post-training improvements in knowledge, understanding, and confidence across all three training modules. Implications of findings are discussed, and further developments outlined.

Introduction of Technology to Support Young People's Care and Mental Health-A Rapid Evidence Review.

Background: Technology and its use within mental health services has advanced dramatically over recent years. Opportunities for mental health services to utilise technology to introduce novel, effective, and more efficient means of delivering assessment, and treatment are increasing. Objective: The current rapid-evidence paper reviews evidence regarding the introduction of novel technology to support young people's mental health and psychological well-being. Methods: A rapid evidence review was conducted. PSYCHINFO and CINAHL were searched for research articles between 2016 and 2021 that were specific to young people, mental health, and technology developments within this domain. N = 27 studies which explored the introduction, feasibility, and value of technology for mental health purposes were included in a narrative synthesis. Quality or risk of bias analyses were not completed. Results: Overall, technological advancements in young people's care were considered positive and engaging for young people. Factors including resources, efficiency of care, engagement, therapeutic effectiveness, ethical considerations, therapeutic alliance, and flexibility were considered within this review. Nevertheless, potential barriers include clinician concerns, socioeconomic factors, and motivation. Conclusion: Effective and sustained use of technology within young people's mental health services will depend on the technology's usability, efficiency, and ability to engage young people. This paper expands on existing research by reviewing a broader range of technology proposed to support young people's mental health and well-being. This will assist in the application of novel technological advancements by indicating effectiveness, preferences, potential barriers, and recommendations for the feasibility and efficacy of introducing technology into young people's services.

Prediction of visual function from automatically quantified optical coherence tomography biomarkers in patients with geographic atrophy using machine learning.

Geographic atrophy (GA) is a vision-threatening manifestation of age-related macular degeneration (AMD), one of the leading causes of blindness globally. Objective, rapid, reliable, and scalable quantification of GA from optical coherence tomography (OCT) retinal scans is necessary for disease monitoring, prognostic research, and clinical endpoints for therapy development. Such automatically quantified biomarkers on OCT are likely to further elucidate structure-function correlation in GA and thus the pathophysiological mechanisms of disease development and progression. In this work, we aimed to predict visual function with machine-learning applied to automatically acquired quantitative imaging biomarkers in GA. A post-hoc analysis of data from a clinical trial and routine clinical care was conducted. A deep-learning automated segmentation model was applied on OCT scans from 476 eyes (325 patients) with GA. A separate machine learning prediction model (Random Forest) used the resultant quantitative OCT (qOCT) biomarkers to predict cross-sectional visual acuity under standard (VA) and low luminance (LLVA). The primary outcome was regression coefficient (r2) and mean absolute error (MAE) for cross-sectional VA and LLVA in Early Treatment Diabetic Retinopathy Study (ETDRS) letters. OCT parameters were predictive of VA (r2 0.40 MAE 11.7 ETDRS letters) and LLVA (r2 0.25 MAE 12.1). Normalised random forest feature importance, as a measure of the predictive value of the three constituent features of GA; retinal pigment epithelium (RPE)-loss, photoreceptor degeneration (PDR), hypertransmission and their locations, was reported both on voxel-level heatmaps and ETDRS-grid subfields. The foveal region (46.5%) and RPE-loss (31.1%) had greatest predictive importance for VA. For LLVA, however, non-foveal regions (74.5%) and PDR (38.9%) were most important. In conclusion, automated qOCT biomarkers demonstrate predictive significance for VA and LLVA in GA. LLVA is itself predictive of GA progression, implying that the predictive qOCT biomarkers provided by our model are also prognostic.

Exploiting species specificity to understand the tropism of a human-specific toxin.

Many pathogens produce virulence factors that are specific toward their natural host. Clinically relevant methicillin-resistant Staphylococcus aureus (MRSA) isolates are highly adapted to humans and produce an array of human-specific virulence factors. One such factor is LukAB, a recently identified pore-forming toxin that targets human phagocytes by binding to the integrin component CD11b. LukAB exhibits strong tropism toward human, but not murine, CD11b. Here, phylogenetics and biochemical studies lead to the identification of an 11-residue domain required for the specificity of LukAB toward human CD11b, which is sufficient to render murine CD11b compatible with toxin binding. CRISPR-mediated gene editing was used to replace this domain, resulting in a "humanized" mouse. In vivo studies revealed that the humanized mice exhibit enhanced susceptibility to MRSA bloodstream infection, a phenotype mediated by LukAB. Thus, these studies establish LukAB as an important toxin for MRSA bacteremia and describe a new mouse model to study MRSA pathobiology.

SELECT-2: a phase II, double-blind, randomized, placebo-controlled study to assess the efficacy of selumetinib plus docetaxel as a second-line treatment of patients with advanced or metastatic non-small-cell lung cancer.

BACKGROUND: Combination of selumetinib plus docetaxel provided clinical benefit in a previous phase II trial for patients with KRAS-mutant advanced non-small-cell lung cancer (NSCLC). The phase II SELECT-2 trial investigated safety and efficacy of selumetinib plus docetaxel for patients with advanced or metastatic NSCLC. PATIENTS AND METHODS: Patients who had disease progression after first-line anti-cancer therapy were randomized (2 : 2 : 1) to selumetinib 75 mg b.i.d. plus docetaxel 60 or 75 mg/m2 (SEL + DOC 60; SEL + DOC 75), or placebo plus docetaxel 75 mg/m2 (PBO + DOC 75). Patients were initially enrolled independently of KRAS mutation status, but the protocol was amended to include only patients with centrally confirmed KRAS wild-type NSCLC. Primary end point was progression-free survival (PFS; RECIST 1.1); statistical analyses compared each selumetinib group with PBO + DOC 75 for KRAS wild-type and overall (KRAS mutant or wild-type) populations. RESULTS: A total of 212 patients were randomized; 69% were KRAS wild-type. There were no statistically significant improvements in PFS or overall survival for overall or KRAS wild-type populations in either selumetinib group compared with PBO + DOC 75. Overall population median PFS for SEL + DOC 60, SEL + DOC 75 compared with PBO + DOC 75 was 3.0, 4.2, and 4.3 months, HRs: 1.12 (90% CI: 0.8, 1.61) and 0.92 (90% CI: 0.65, 1.31), respectively. In the overall population, a higher objective response rate (ORR; investigator assessed) was observed for SEL + DOC 75 (33%) compared with PBO + DOC 75 (14%); odds ratio: 3.26 (90% CI: 1.47, 7.95). Overall the tolerability profile of SEL + DOC was consistent with historical data, without new or unexpected safety concerns identified. CONCLUSION: The primary end point (PFS) was not met. The higher ORR with SEL + DOC 75 did not translate into prolonged PFS for the overall or KRAS wild-type patient populations. No clinical benefit was observed with SEL + DOC in KRAS wild-type patients compared with docetaxel alone. No unexpected safety concerns were reported. TRIAL IDENTIFIER: Clinicaltrials.gov NCT01750281.

Biological response to hormonal manipulation in oestrogen receptor positive ductal carcinoma in situ of the breast.

Adjuvant antioestrogen therapy with tamoxifen is recommended for all women following breast-conserving surgery for ductal carcinoma in situ (DCIS) to reduce local recurrence, despite 50% of lesions being oestrogen receptor (OR) negative. We have investigated the response to hormone manipulation in DCIS by studying changes in epithelial proliferation and progesterone receptor (PR) expression as surrogate molecular markers of treatment effects in DCIS of known OR status. Women were identified who had undergone diagnostic core biopsy followed by surgery for DCIS 14-41 days later. Ki67 (a measure of epithelial cell proliferation) and PR expression were determined by immunohistochemistry on paired paraffin sections of the core biopsy and operative specimens for each patient, with OR and HER-2 measured on the operative specimen. Women were divided into three groups according to whether they had changed hormone therapy (stopped hormone replacement therapy (HRT), group 1), continued taking HRT (group 2) or were not taking HRT (group 3) between core biopsy and surgery. In OR-positive (but not in OR-negative) DCIS after oestrogen withdrawal (group 1), a fall in the mean cell proliferation (P&<0.01) was observed. A fall in PR expression between core biopsy and surgery was also seen in this group (P=0.02). No change in either mean cell proliferation or PR expression was seen in the other two groups in OR-positive or -negative DCIS. The fall in proliferation and PR expression occurred regardless of HER-2 status. In conclusion, a biological response to hormone manipulation is only seen in OR-positive DCIS tumours. Any clinical value of antioestrogen therapy is likely to be restricted to this group.

Copper supplementation has no effect on markers of DNA damage and liver function in healthy adults (FOODCUE project).

BACKGROUND/AIMS: Copper is routinely used in the laboratory to promote oxidation in vitro. However, copper concentrations are million-fold higher than physiological concentrations and, in contrast, accumulating evidence suggests that copper may have an antioxidant role in vivo. The aim of this study was to provide data on how increased intake of copper affected mononuclear leukocyte DNA damage and liver function in healthy young free-living men and women. METHODS: The study design was a double-blind repeated crossover trial with treatment and intervening placebo periods, each of 6 weeks' duration. The following supplementations were given orally in sequence: CuSO(4) at a dose of 3 mg copper/day and copper amino acid chelates at doses of 3 and 6 mg copper/day. Oxidative DNA damage was assessed using a modification of the alkaline Comet assay incorporating an endonuclease III digestion step. The assessment of liver function was by measurement of the liver enzymes, alanine aminotransferase and L-gamma-glutamyltransferase. RESULTS: There was no significant alteration in mononuclear leukocyte DNA damage or on liver function after 6 weeks of copper supplementation at two doses (3 and 6 mg/day). CONCLUSIONS: Copper supplementation (giving total copper intake at the highest level of 7 mg/day) did not induce DNA damage or adversely affect liver function in healthy adults.

Dichlorobis(dibenzylamino)bis(tetrahydrofuran)zirconium(IV) toluene hemisolvate.

The title complex, [ZrCl2(C4H8O)2(C14H14N)2].0.5C7H8, was prepared in an unusual manner by utilizing [Mg[N(CH2Ph)2]2] as a ligand transfer reagent. The Zr atom lies in a distorted octahedral environment where steric repulsion from the large dibenzylamino ligands leads to a widening of the N-Zr-N angle [99.95 (9) degrees ] and corresponding compression of other angles [Cl-Zr-Cl 160.95 (3) degrees and O-Zr-O 78.22 (7) degrees ]. This distortion is compared with those found in the previously determined structures of the dimethylamino and diethylamino analogues.

Electrophoretic behaviour of oligonucleotides and mono-, di- and triphosphate nucleotides by capillary zone electrophoresis.

A systematic investigation has been made into the mechanisms of the capillary zone electrophoresis (CZE) separation of 12 common nucleotides (mono-, di- and triphosphorylated) and polydeoxythymidylic acid oligonucleotides (pd(T)5-18) using electrophoretic mobility values calculated from migration time data. Relationships between electrophoretic mobility and the physicochemical characteristics of the analytes (charge, dissociation constants, charge-to-mass ratio) and the background electrolyte conditions (buffer strength, percentage organic modifier and buffer pH) were characterised. Nucleotide migration was dominated by the negatively charged phosphate groups. Additionally, there were important contributions to migration behaviour from the ionised amide groups of the nucleobases guanine and uracil at higher buffer pH values or with the presence of methanol in the electrolyte. Calculated electrophoretic mobility values for the nucleotides showed a substantially improved (5-fold) inter-run repeatability compared with migration time data. These studies show the value of representing nucleotide migration data as electrophoretic mobility in CZE for obtaining a more thorough analysis of separation mechanisms and to compensate for variation in migration time data caused by small changes in electrosmotic flow. Oligonucleotides pd(T)5-11 could be adequately resolved from their nearest neighbour, but the limit of single-base separation was pd(T)10 from pd(T)11 under the conditions used. It was calculated that a difference in charge-to-mass ratio of 2.64 x 10(-5) was required for resolution under the CZE conditions used.

Copper supplementation in humans does not affect the susceptibility of low density lipoprotein to in vitro induced oxidation (FOODCUE project).

The oxidative modification of low-density lipoprotein cholesterol (LDL) has been implicated in the pathogenesis of atherosclerosis. Copper (Cu) is essential for antioxidant enzymes in vivo and animal studies show that Cu deficiency is accompanied by increased atherogenesis and LDL susceptibility to oxidation. Nevertheless, Cu has been proposed as a pro-oxidant in vivo and is routinely used to induce lipid peroxidation in vitro. Given the dual role of Cu as an in vivo antioxidant and an in vitro pro-oxidant, a multicenter European study (FOODCUE) was instigated to provide data on the biological effects of increased dietary Cu. Four centers, Northern Ireland (coordinator), England, Denmark, and France, using different experimental protocols, examined the effect of Cu supplementation (3 or 6 mg/d) on top of normal Cu dietary intakes or Cu-controlled diets (0.7/1.6/6.0 mg/d), on Cu-mediated and peroxynitrite-initiated LDL oxidation in apparently healthy volunteers. Each center coordinated its own supplementation regimen and all samples were subsequently transported to Northern Ireland where lipid peroxidation analysis was completed. The results from all centers showed that dietary Cu supplementation had no effect on Cu- or peroxynitrite-induced LDL susceptibility to oxidation. These data show that high intakes (up to 6 mg Cu) for extended periods do not promote LDL susceptibility to in vitro-induced oxidation.

Response of putative indices of copper status to copper supplementation in human subjects.

No sensitive functional index is currently available to assess Cu status in healthy human populations. This study evaluated the effect of Cu supplementation on putative indices of Cu status in twelve women and twelve men, aged between 22 and 45 years, who participated in a double-blind placebo controlled crossover study. The study consisted of three 6-week supplementation regimens of 3 mg CuSO4, 3 mg Cu-glycine chelate and 6 mg Cu-glycine chelate, each separated by placebo periods of equal length. Women had significantly higher caeruloplasmin oxidase activity (P < 0.001), caeruloplasmin protein concentration (P < 0.05), and serum diamine oxidase activity (P < 0.01) at baseline than men. Erythrocyte and leucocyte superoxide dismutase activity, leucocyte cytochrome c oxidase activity, and erythrocyte glutathione peroxidase activity did not respond to Cu supplementation. Platelet cytochrome c oxidase activity was significantly higher (P < 0.01), after supplementation with 6 mg Cu-glycine chelate in the total group and in women but did not change in men. Caeruloplasmin oxidase activity was significantly higher (P < 0.05), in men after supplementation with 3 mg Cu-glycine chelate, while caeruloplasmin protein concentration was significantly lower in men after supplementation with 6 mg Cu-glycine chelate (P < 0.05). Serum diamine oxidase activity was significantly higher after all supplementation regimens in the total group and in both men and women (P < 0.01). These results indicate that serum diamine oxidase activity is sensitive to changes in dietary Cu intakes and may also have the potential to evaluate changes in Cu status in healthy adult human subjects.

Allocation of crania to groups via the "new morphometry".

An investigation regarding the variation in cranial morphology between American blacks and whites was conducted using triangulation schemes of inter-landmark distances and converting these to three dimensional coordinate data. A least squares superimposition method and Euclidean distance analysis were utilized to obtain parameters for classifying individuals in our sample, consisting of 19 black and nineteen white crania from the William M. Bass, III Donated and Forensic collections curated at the University of Tennessee, Knoxville. Thirty-six caliper measurements were collected on each skull based on 14 homologous cranial landmarks (nasion, bregma, lambda, prosthion, subspinale, basion, frontomalare (left and right), zygoorbitale (left and right), zygotemporale (left and right), and left and right asterion). The results are compared to traditional discriminant analysis. The classification results using the new morphometry are comparable to traditional discriminant analysis. However, the new morphometry can provide information as to the specific location of morphological variation that cannot be obtained with discriminant analysis.

A preliminary investigation of postmortem tooth loss.

Forensic anthropologists have found a seemingly increased frequency of dismemberment cases and subsequent scattering of the elements that mandates developing unconventional methods of estimating postmortem interval. The chronological sequence in postmortem tooth loss has been investigated as an indicator for estimation of time since death. The anterior dentitions of cadavera were observed to discern patterns in "drop time" based on age, periodontal health, seasonality and location of body placement. Individuals deposited in the summer months lost teeth much more rapidly than those deposited in the late fall or winter months. Similarly, individuals exposed to direct sunlight, a micro-environment where rapid decomposition has been noted, lost teeth before individuals in shaded locales. Since tooth loss is dependent on the deterioration of the soft tissues which bind the tooth into the alveolar bone, we found tooth loss to be correlated with general soft tissue decomposition rates as dictated by season and environment. When utilized as sole indicator, the patterns of postmortem tooth loss can not be used for estimating time since death. However, when used in conjunction with other indicators, tooth loss patterns may provide useful information for more accurate estimation of the postmortem interval.

Pulsed-dye laser treatment of vascular lesions.

Pulsed-dye laser therapy can effectively treat port-wine stains and telangiectases. Nursing considerations include pre- and post-operative assessment and care, contraindications, and special concerns for the pediatric patient.