Effectiveness of systematically delivered evidence-based home safety promotion to improve child home safety practices: a controlled before-and-after study.

OBJECTIVE: Evaluate the effectiveness of systematically delivered evidence-based home safety promotion for improving child home safety practices. DESIGN: Controlled before-and-after study. SETTING: Nine electoral wards in Nottingham, UK. PARTICIPANTS: 361 families with children aged 2-7 months at recruitment living in four intervention wards with high health, education and social need; and 401 in five matched control wards. INTERVENTION: Evidence-based home safety promotion delivered by health visiting teams, family mentors and children's centres including 24 monthly safety messages; home safety activity sessions; quarterly 'safety weeks'; home safety checklists. OUTCOMES: Primary: composite measure comprising having a working smoke alarm, storing poisons out of reach and having a stairgate. Secondary: other home safety practices; medically attended injuries. Parents completed questionnaires at 12 and 24 months after recruitment plus optional three monthly injury questionnaires. RESULTS: At 24 months there was no significant difference between groups in the primary outcome (55.8% vs 48.8%; OR 1.58, 95% CI 0.98 to 2.55) or medically attended injury rates (incidence rate ratio 0.89, 95% CI 0.51 to 1.56), but intervention families were more likely to store poisons safely (OR 1.81, 95% CI 1.06 to 3.07), have a fire escape plan (OR 1.81, 95% CI 1.06 to 3.08), use a fireguard or have no fire (OR 3.17, 95% CI 1.63 to 6.16) and perform more safety practices (ß 0.46, 95% CI 0.13 to 0.79). CONCLUSIONS: Systematic evidence-based home safety promotion in areas with substantial need increases adoption of some safety practices. Funders should consider commissioning evidence-based multicomponent child home safety interventions. TRIAL REGISTRATION NUMBER: ISRCTN31210493.

Customizable landmark-based field aperture design for automated whole-brain radiotherapy treatment planning.

PURPOSE: To develop and evaluate an automated whole-brain radiotherapy (WBRT) treatment planning pipeline with a deep learning-based auto-contouring and customizable landmark-based field aperture design. METHODS: The pipeline consisted of the following steps: (1) Auto-contour normal structures on computed tomography scans and digitally reconstructed radiographs using deep learning techniques, (2) locate the landmark structures using the beam's-eye-view, (3) generate field apertures based on eight different landmark rules addressing different clinical purposes and physician preferences. Two parallel approaches for generating field apertures were developed for quality control. The performance of the generated field shapes and dose distributions were compared with the original clinical plans. The clinical acceptability of the plans was assessed by five radiation oncologists from four hospitals. RESULTS: The performance of the generated field apertures was evaluated by the Hausdorff distance (HD) and mean surface distance (MSD) from 182 patients' field apertures used in the clinic. The average HD and MSD for the generated field apertures were 16 ± 7 and 7 ± 3 mm for the first approach, respectively, and 17 ± 7 and 7 ± 3 mm, respectively, for the second approach. The differences regarding HD and MSD between the first and the second approaches were 1 ± 2 and 1 ± 3 mm, respectively. A clinical review of the field aperture design, conducted using 30 patients, achieved a 100% acceptance rate for both the first and second approaches, and the plan review achieved a 100% acceptance rate for the first approach and a 93% acceptance rate for the second approach. The average acceptance rate for meeting lens dosimetric recommendations was 80% (left lens) and 77% (right lens) for the first approach, and 70% (both left and right lenses) for the second approach, compared with 50% (left lens) and 53% (right lens) for the clinical plans. CONCLUSION: This study provided an automated pipeline with two field aperture generation approaches to automatically generate WBRT treatment plans. Both quantitative and qualitative evaluations demonstrated that our novel pipeline was comparable with the original clinical plans.

Evaluation of the effectiveness, implementation and cost-effectiveness of the Stay One Step Ahead home safety promotion intervention for pre-school children: a study protocol.

BACKGROUND: Unintentional injuries in children under the age of 5 years commonly occur in the home and disproportionately affect those living in disadvantaged circumstances. Targeted home safety promotion should be offered to families most at risk but there is a paucity of standardised evidence-based resources available for use across family-support practitioners. OBJECTIVE: To assess the effectiveness, implementation and cost-effectiveness of a 2-year home safety programme (Stay One Step Ahead) developed by parents, practitioners and researchers, and delivered by a range of family support providers in inner-city localities, compared with usual care in matched control localities. METHODS: Parents of children aged 0 to 7 months will be recruited to a controlled before and after observational study. The primary outcome is home safety assessed by the proportion of families with a fitted and working smoke alarm, safety gate on stairs (where applicable) and poisons stored out of reach, assessed using parent-administered questionnaires at baseline, 12 and 24 months.Secondary outcomes include: the impact on other parent-reported safety behaviours, medically-attended injuries, self-efficacy for home safety and knowledge of child development and injury risk using questionnaires and emergency department attendance data; implementation (reach, acceptability, barriers, facilitators) of home safety promotion assessed through interviews and observations; and cost-effectiveness using medically-attended injury costs ascertained from healthcare records. CONCLUSION: If shown to be effective and cost-effective this study will provide a practical resource to underpin national guidance. The study could inform public health prevention strategies to reduce home injury in children most at risk, while delivering cost savings to health and care services. TRIAL REGISTRATION NUMBER: ISRCTN31210493; Pre result.

Cdc37/Hsp90 protein complex disruption triggers an autophagic clearance cascade for TDP-43 protein.

The RNA-binding protein, trans-active response DNA-binding protein 43 (TDP-43), is normally found in the nucleus, but in amyotrophic lateral sclerosis, frontal temporal dementia, and some cases of Alzheimer disease it is cleaved and mislocalized to the cytosol, leading to accumulation. The mechanisms contributing to this are largely unknown. Here, we show that part of the normal clearance cascade for TDP-43 involves the Cdc37/Hsp90 complex. An Hsp90 inhibitor that disrupts the Cdc37/Hsp90 complex reduced TDP-43 levels to a greater extent than a standard Hsp90 ATPase inhibitor. When Cdc37 was depleted, TDP-43 underwent proteolytic clearance that was dependent on nuclear retrotranslocation and autophagic uptake. Accumulation of the microtubule-associated protein tau prevented the clearance of cleaved TDP-43, but not its production. This caused cleaved TDP-43 to accumulate, a feature observed in the brain of persons with Alzheimer disease. Clearance of cleaved TDP-43 was also prevented by knockdown of the autophagic inducer beclin1. Thus, in cells where TDP-43 clearance is normally needed, a system that employs manipulation of the Hsp90 complex and autophagy exists. But when tau accumulation is occurring, cleaved TDP-43 can no longer be cleared, perhaps explaining the emergence of these co-pathologies.

Regulatory T cells in the peripheral blood of women with gestational diabetes: a systematic review and meta-analysis.

Background: Gestational diabetes (GDM) affects approximately 14% of pregnancies globally and is associated with short- and long-term complications for both the mother and child. In addition, GDM has been linked to chronic low-grade inflammation with recent research indicating a potential immune dysregulation in pathophysiology and a disparity in regulatory T cells. Objective: This systematic review and meta-analysis aimed to determine whether there is an association between GDM and the level of Tregs in the peripheral blood. Methods: Literature searches were conducted in PubMed, Embase, and Ovid between the 7th and 14th of February 2022. The inclusion criteria were any original studies published in the English language, measuring differentiated Tregs in women with GDM compared with glucose-tolerant pregnant women. Meta-analysis was performed between comparable Treg markers. Statistical tests were used to quantify heterogeneity: τ 2, χ 2, and I 2. Study quality was assessed using a modified version of the Newcastle-Ottawa scale. Results: The search yielded 223 results: eight studies were included in the review and seven in the meta-analysis (GDM = 228, control = 286). Analysis of Tregs across all trimesters showed significantly lower Treg numbers in women with GDM (SMD, -0.76; 95% CI, -1.37, -0.15; I 2 = 90%). This was reflected in the analysis by specific Treg markers (SMD -0.55; 95% CI, -1.04, -0.07; I 2 = 83%; third trimester, five studies). Non-significant differences were found within subgroups (differentiated by CD4+FoxP3+, CD4+CD127-, and CD4+CD127-FoxP3) of both analyses. Conclusion: GDM is associated with lower Treg numbers in the peripheral maternal blood. In early pregnancy, there is clinical potential to use Treg levels as a predictive tool for the subsequent development of GDM. There is also a potential therapeutic intervention to prevent the development of GDM by increasing Treg populations. However, the precise mechanism by which Tregs mediate GDM remains unclear. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42022309796.

Fully-automated, CT-only GTV contouring for palliative head and neck radiotherapy.

Planning for palliative radiotherapy is performed without the advantage of MR or PET imaging in many clinics. Here, we investigated CT-only GTV delineation for palliative treatment of head and neck cancer. Two multi-institutional datasets of palliative-intent treatment plans were retrospectively acquired: a set of 102 non-contrast-enhanced CTs and a set of 96 contrast-enhanced CTs. The nnU-Net auto-segmentation network was chosen for its strength in medical image segmentation, and five approaches separately trained: (1) heuristic-cropped, non-contrast images with a single GTV channel, (2) cropping around a manually-placed point in the tumor center for non-contrast images with a single GTV channel, (3) contrast-enhanced images with a single GTV channel, (4) contrast-enhanced images with separate primary and nodal GTV channels, and (5) contrast-enhanced images along with synthetic MR images with separate primary and nodal GTV channels. Median Dice similarity coefficient ranged from 0.6 to 0.7, surface Dice from 0.30 to 0.56, and 95th Hausdorff distance from 14.7 to 19.7 mm across the five approaches. Only surface Dice exhibited statistically-significant difference across these five approaches using a two-tailed Wilcoxon Rank-Sum test (p ≤ 0.05). Our CT-only results met or exceeded published values for head and neck GTV autocontouring using multi-modality images. However, significant edits would be necessary before clinical use in palliative radiotherapy.

Analysis of a panel-based pharmacogenomics testing program among members of a commercial and Medicare client of a pharmacy benefits manager.

BACKGROUND: Although the field of pharmacogenomics (PGx) has existed for decades, use of pharmacogenomic information by providers to optimize medication therapy for patients has had relatively slow adoption. There are many factors that have contributed to the slow adoption of PGx testing, but it is partially due to a lack of coverage by payers. If PGx testing is covered by payers, frequently only testing of a specific gene is covered, rather than a panel of many genes. As a result, little is known about how coverage of a panel-based PGx test will affect a member's medication therapy. OBJECTIVES: To determine how giving providers specific medication optimization recommendations, based on results of a panel-based PGx test, impacted members' medication regimens. METHODS: Pharmacy claims data were retrospectively reviewed for this exploratory study. Members who participated in PGx testing were in the intervention group and members who chose not to participate in the PGx testing, but who were eligible to participate, were in the control group. PGx test results, including suggested medication changes, were mailed to providers. To determine if providers adopted the suggested medication changes, pharmacy claims data were analyzed retrospectively for the 4-month period preceding and following the date from which recommendations were provided to prescribers. RESULTS: Of the 101 members included in the analysis, 50 were in the intervention group and 51 were in the control group. In the intervention group, members were taking in a total of 352 medications; 165 of the medications had PGx guidance. Based on the PGx test results, 62 of these medications (37.6%) had recommendations. Of members who received PGx testing, 76% had at least 1 recommended change. When pharmacist recommendations were made, a change was made to the medication 27% of the time. There was a statistically significant difference between the number of medication changes in the PGx group and the control group (P = 0.024). CONCLUSIONS: Recommendations based on PGx testing can lead to changes in medications and an optimized medication regimen for members. DISCLOSURES: The authors have no conflicts to disclose that may present a potential conflict of interest.

Research in the Healthcare Design Practice: Design Practitioners' Perspective.

OBJECTIVE: This study explores design practitioners' level of knowledge about research, their attitude toward research integration into the design practice, and the barriers to its application in the design process. BACKGROUND: Design practitioners tend to heavily rely on previous design experience and precedents rather than utilization and application of research. Research can facilitate the evaluation and creation of innovative design solutions. Integrating research has been a challenge for the design industry. METHODOLOGY: The study utilized an online survey to solicit feedback from architects and interior designers in the healthcare sector through a snowball sampling approach. The survey comprised closed-ended and open-ended questions categorized into three distinct sections, each focusing on one of the study objectives. A total of 115 participants completed the questionnaire. RESULTS: Practitioners tend to integrate research into the early design phases and programming. It is recognized as a tool for design enhancement by 62%, while 7% considered it to be a hindrance to their creativity. Primary data collection methods include collaboration with colleagues and user groups rather than journals and trade magazines. Cost, time, and lack of expertise are the top three hurdles in applying research in practice. CONCLUSIONS: Practitioners have a positive attitude toward research, perceive it as an impactful design enhancement tool, and use it to promote their credibility. Lack of research expertise hinders the use and conduct of research. According to design practitioners, research is costly and time-consuming and impedes their ability to fulfill clients' goals and the project timeline.

Intranasal Human Growth Hormone (hGH) Induces IGF-1 Levels Comparable With Subcutaneous Injection With Lower Systemic Exposure to hGH in Healthy Volunteers.

CONTEXT: The development of an improved, efficacious human GH (hGH) product administered by a noninjectable route of delivery such as the nasal route is highly desirable. We have developed a novel nasal hGH product (CP024) that showed excellent nasal absorption in animal models; however, the translation of these results into the clinical setting is essential because past attempts to develop such formulations by other groups have been unable to induce IGF-1 in man. OBJECTIVE: The objective of the study was to assess the pharmacokinetics, pharmacodynamics, and tolerability of CP024 compared with a sc hGH injection. DESIGN: This was a single-center, nonrandomized placebo-controlled, open-label, five-way crossover study in eight healthy volunteers. SETTING: The study was carried out at a contract research organization, Quotient Bioresearch. VOLUNTEERS: Eight healthy male volunteers, given an iv infusion of octreotide to suppress the endogenous GH secretion during the study period, participated in the study. No volunteers were withdrawn due to side effects. MAIN OUTCOME MEASURES: Measurement of hGH and IGF-1 levels and tolerability of the drug product was performed. RESULTS: No serious adverse events were reported and no subjects withdrawn from study due to the treatment. After the nasal administration of CP024, 3-fold higher hGH blood levels were obtained as compared with hGH nasal control. The relative bioavailability was about 3%. CP024 (given twice daily) induced a significant increase in IGF-1 levels up to 19 hours after administration, with no significant difference to those obtained after the sc injection of hGH. CONCLUSIONS: The study indicates that CP024 is a promising candidate for an efficacious nasal product for the treatment of GH deficiency due to induction of IGF-1 similar to that after a sc injection, despite the lower plasma hGH concentration obtained. A dose-response study is needed to evaluate the optimal nasal dose.

Sarcomere strain and heterogeneity correlate with injury to frog skeletal muscle fiber bundles.

Sarcomere length and first-order diffraction line width were measured by laser diffraction during elongation of activated frog tibialis anterior muscle fiber bundles (i.e., eccentric contraction) at nominal fiber strains of 10, 25, or 35% (n = 18) for 10 successive contractions. Tetanic tension, measured just before each eccentric contraction, differed significantly among strain groups and changed dramatically during the 10-contraction treatment (P < 0.01). Average maximum tetanic tension for the three groups measured before any treatment was 203.7 +/- 6.8 kN/m2, but after the 10-eccentric contraction sequence decreased to 180.3 +/- 3.8, 125.1 +/- 7.8, and 78.3 +/- 5.1 kN/m2 for the 10, 25, and 35% strain groups, respectively (P < 0.0001). Addition of 10 mM caffeine to the bathing medium decreased the loss of tetanic tension in the 10% strain group but had only a minimal effect on either the 25 or 35% strain groups. Diffraction pattern line width, a measure of sarcomere length heterogeneity, increased significantly with muscle activation and then continued to increase with successive stretches of the activated muscle. Line width increase after each stretch was significantly correlated with the lower yield tension of the successive contractile record. These data demonstrate a direct association and, perhaps, a causal relationship between sarcomere strain and fiber bundle injury. They also demonstrate that muscle injury is accompanied by a progressive increase in sarcomere length heterogeneity, yielding lower yield tension as injury progresses.

Fetuin-A triggers the secretion of a novel set of exosomes in detached tumor cells that mediate their adhesion and spreading.

Our goal in this study was to define the mechanisms by which fetuin-A mediates the adhesion of tumor cells. The data show that in the absence of fetuin-A, detached tumor cells secrete exosomes that contain most of the known exosomal associated proteins but lack the capacity to mediate cellular adhesion. In the presence of fetuin-A, the cells secrete exosomes, which contain, in addition to the other exosomal proteins, fetuin-A, plasminogen and histones. These exosomes mediate adhesion and cell spreading. Plasminogen is a participant in this novel adhesion mechanism. The data suggest that these exosomes play a role in tumor progression.

Detachment of breast tumor cells induces rapid secretion of exosomes which subsequently mediate cellular adhesion and spreading.

Exosomes are nano-vesicles secreted by a wide range of mammalian cell types. These vesicles are abundant in serum and other extracellular fluids and contain a large repertoire of proteins, mRNA and microRNA. Exosomes have been implicated in cell to cell communication, the transfer of infectious agents, and neurodegenerative diseases as well as tumor progression. However, the precise mechanisms by which they are internalized and/or secreted remain poorly understood. In order to follow their release and uptake in breast tumor cells in real time, cell-derived exosomes were tagged with green fluorescent protein (GFP)-CD63 while human serum exosomes were rhodamine isothiocynate-labeled. We show that detachment of adherent cells from various substrata induces a rapid and substantial secretion of exosomes, which then concentrate on the cell surfaces and mediate adhesion to various extracellular matrix proteins. We also demonstrate that disruption of lipid rafts with methyl-beta-cyclodextrin (MßCD) inhibits the internalization of exosomes and that annexins are essential for the exosomal uptake mechanisms. Taken together, these data suggest that cellular detachment is accompanied by significant release of exosomes while cellular adhesion and spreading are enhanced by rapid uptake and disposition of exosomes on the cell surface.

Complex regulation of store-operated Ca2+ entry pathway by PKC-epsilon in vascular SMCs.

The role of PKC in the regulation of store-operated Ca2+ entry (SOCE) is rather controversial. Here, we used Ca2+-imaging, biochemical, pharmacological, and molecular techniques to test if Ca2+-independent PLA2beta (iPLA2beta), one of the transducers of the signal from depleted stores to plasma membrane channels, may be a target for the complex regulation of SOCE by PKC and diacylglycerol (DAG) in rabbit aortic smooth muscle cells (SMCs). We found that the inhibition of PKC with chelerythrine resulted in significant inhibition of thapsigargin (TG)-induced SOCE in proliferating SMCs. Activation of PKC by the diacylglycerol analog 1-oleoyl-2-acetyl-sn-glycerol (OAG) caused a significant depletion of intracellular Ca2+ stores and triggered Ca2+ influx that was similar to TG-induced SOCE. OAG and TG both produced a PKC-dependent activation of iPLA2beta and Ca2+ entry that were absent in SMCs in which iPLA2beta was inhibited by a specific chiral enantiomer of bromoenol lactone (S-BEL). Moreover, we found that PKC regulates TG- and OAG-induced Ca2+ entry only in proliferating SMCs, which correlates with the expression of the specific PKC-epsilon isoform. Molecular downregulation of PKC-epsilon impaired TG- and OAG-induced Ca2+ influx in proliferating SMCs but had no effect in confluent SMCs. Our results demonstrate that DAG (or OAG) can affect SOCE via multiple mechanisms, which may involve the depletion of Ca2+ stores as well as direct PKC-epsilon-dependent activation of iPLA2beta, resulting in a complex regulation of SOCE in proliferating and confluent SMCs.

Tolerance induction in a large-animal model using total lymphoid irradiation and intrathymic bone marrow.

BACKGROUND: Immunological unresponsiveness of T cells to alloantigen can be induced by intrathymic injection of donor-specific antigen in small-animal models. Intrathymic tolerance to vascularized grafts in large animals has not previously been reported. METHODS: Thirty-two dogs were allocated into dog leukocyte antigen DP locus allele (class II)-matched donor-recipient pairs. Female recipients were paired with male donors. Tissue typing was based on restriction fragment length polymorphism. Recipients were given 18 Gy total lymphoid irradiation in 16 fractions (1.125 Gy each) over 4 weeks. Thoracotomy after the 6th fraction permitted perithymic (n=4) or intrathymic (n=4) injection of donor bone marrow (BM) or intrathymic injection of saline (n=5). Another group received intravenous peripheral BM infusion (n=3). Fifty days postthoracotomy recipients underwent bilateral nephrectomy and donor-specific kidney transplantation. Acute rejection, suspected when serum creatinine was more than 600 mumol/L or urea was more than 40 mmol/L, was confirmed histologically. Full-thickness skin grafts followed more than 100 days posttransplantation. Tissue samples were taken for Y-chromosome polymerase chain reaction. RESULTS: One intrathymic (25%) and three perithymic (75%) BM recipients developed tolerance to renal allografts. Three intrathymic BM recipients rejected after 27, 32, and 54 days and one perithymic BM recipient rejected after 42 days. All recipients given peripheral BM or saline had rejected by 29 and 38 days, respectively. All recipients surviving more than 100 days posttransplantation, accepted donor specific and rejected dog leukocyte antigen-DP locus allele (class II) identical third-party skin grafts. Polymerase chain reaction detected intrathymic but not hematopoietic chimerism in sex-mismatched pairs. CONCLUSIONS: Fractionated total lymphoid irradiation and perithymic or intrathymic donor-specific BM induced tolerance to renal and skin allografts without inducing hematopoietic chimerism.